Synthesis of optically active thromboxane A2 and Leukotriene D4 receptor antagonists

Article abstract of DOI:10.1246/bcsj.20130261

Both (+)- and (-)-4-{[(2-{4-cUorophenylsulfonylamino}-1-{3-[(Q-2-(7-cWoro- 2-quinolyl)-vinyl]phenyl}ethyl)-thio]methyl}benzoic acid (1), Thromboxane A2 and Leukotriene D4 receptor dual antagonist were synthesized. Racemic methyl 4-({[2-amino-1-(3-hydroxym

Full text of DOI:10.1246/bcsj.20130261

© 2013 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 87, No. 1, 127-140 (2014)
127
Synthesis of Optically Active Thromboxane A2 and
Leukotriene D4 Receptor Antagonists
Souichirou Kawazoe,*1,2 Yoshinori Okamoto,3 Masaki Yokota,3 Hirokazu Kubota,3 Ryo Naito,3
Makoto Takeuchi,3 Shigeru Ieda,1 Minoru Okada,1 and Takeshi Oriyama2
1Technology, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001
2Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512
3Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585
Received September 20, 2013; E-mail: souichirou.kawazoe@astellas.com
Both (+)- and (¹)-4-{[(2-{4-chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)-vinyl]phenyl}ethyl)-
thio]methyl}benzoic acid (1), Thromboxane A2 and Leukotriene D4 receptor dual antagonist were synthesized. Racemic
methyl 4-({[2-amino-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)benzoate (2), and methyl 4-[({2-amino-1-[3-(1,3-
dioxolan-2-yl)phenyl]ethyl}thio)methyl]benzoate (3) were derived from 2-(3-bromophenyl)-1,3-dioxolane (4). Com-
pound 2 was resolved via di-p-toluoyl-D/L-tartaric acid salts to transform to (+)- and (¹)-1, respectively. We also
demonstrated that one optically active salt of compound 2 was converted to optically active (+)-1 without chromatography
purification.
Thromboxane A2 (TXA2) and Leukotriene D4 (LTD4) are
chemical mediators associated with inflammatory and respira-
tory diseases, and antagonists of both chemicals are used
for the treatment of asthma.1 TXA2 and LTD4 dual receptor
antagonists have also been investigated with their potent effi-
cacy,2 and 4-{[(2-{4-chlorophenylsulfonylamino}-1-{3-[(E)-2-
(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic
acid (1) (Figure 1) has been identified as an orally active dual
antagonist among the chloroquinolylvinylbenzene derivatives.3
Given that one of the optically active compounds in a racemate
generally has higher activity than the other, the TXA2 and LTD4
antagonistic activities of both enantiomers must be confirmed.
After determination of biological activity, we used optical
resolution as the first scalable synthetic route for compound
1 to create a scalable synthetic route to provide one of these
optically active candidates.
tion of amino moiety, and then the hydroxy group was
mesylated. The substitution reaction of mesylate 9 with methyl
4-sulfanylmethylbenzoate (10) afforded the intermediate 11
with low yield due to the side product resulting from the
elimination of the mesylate. Column chromatography purifica-
tion was necessary to remove impurities. After the methyl-
hydrazine treatment of phthalimide 11, the generated amino
moiety was sulfonated with 4-chlorobenzenesulfonyl chloride
(13) to give 14, which was hydrolyzed to afford 1. However,
several disadvantages were encountered with this route, such as
the use of a protection group and the need for chromatography
purification. We were unable to achieve optical resolution
of the intermediate amino alcohol 6 with crystallization as
optically active salts, and due to these limitations, an alternative
synthetic route was desired.
We first attempted synthesis of the 1-phenyl-2-aminoethyl
sulfide via nucleophilic thiol addition to 2-phenylazirizine
derivatives. The nucleophilic addition proceeded smoothly, but
the regioselective azirizine opening reaction did not occur.
Next, we planned to resolve the key intermediate 1-phenyl-2-
aminoethyl sulfide backbones 2 and 3. These amines were
prepared by reduction of the nitro group after addition of thiol
10 to nitrostyrenes derived from bromide 4. Several chloro-
quinolylvinylbenzenes have been previously reported as inter-
mediates in the synthesis of LTD4 receptor antagonists. We
considered two possible approaches to synthesizing 7-chloro-
quinolylvinylbenzenes: condensation of 7-chloroquinaldine
(25) and benzaldehyde derivatives,3,4a and Heck reaction of
7-chloro-2-vinylquinoline and a bromobenzene derivative in
the late stage.4b We attempted the condensation approach
between compound 25 and benzaldehyde derivatives®methyl
4-({[2-(4-chlorophenylsulfonylamino)-1-(3-formylphenyl)eth-
yl]thio}methyl)benzoate (23) and methyl 4-({[1-(3-formyl-
In the discovery route, 11 steps overall from 5 were required
for racemic 1 (Schemes 1 and 2). Synthesis of amino alcohol 6
involved 5 steps. The phthalimide group was used for protec-
O
OH
Cl
S
H
N
S
Cl
N
O
O
1
Figure 1.
Published on the web October 31, 2013; doi:10.1246/bcsj.20130261

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Thromboxane A2 and Leukotriene D4 Receptor Antagonists
O
OH
5 steps
OHC
OMe
NH2
Cl
N
5
6
Scheme 1.
O
O
O
OH
OH
O
7
N
NH2
Cl
N
Cl
N
toluene
O
6
8
O
O
HS
OMe
OMs
10
MsCl, Pyridine
ClCH2CH2Cl
N
Cl
N
Cs2CO3
DMSO
O
9
O
OMe
O
OMe
MeHNNH2
O
N
S
S
1,4-Dioxane
EtOH
NH2
Cl
N
Cl
N
O
11
12
O
S
OMe
4-ClC6H4SO2Cl (13)
Et3N
Cl
1M NaOH
THF, MeOH
H
1
N
ClCH2CH2Cl
S
Cl
N
O
O
14
Scheme 2.
phenyl)-2-nitroethyl]thio}methyl)benzoate (24)®to synthesize
compound 1.
to afford 15 in 58% yield. The aldehyde 15 was reduced with
NaBH4 in MeOH to give primary alcohol 16,6d which was
treated with HCl(aq) in situ to afford 17 in 66% yield after silica
gel chromatography purification (Scheme 3). When m-phthal-
aldehyde was partially reduced with NaBH4 to afford compound
17 in 58% yield, purification with silica gel chromatography
was necessary.6c
In another segment of the experiment methyl 4-sulfanyl-
methylbenzoate (10) was derived from benzyl bromide 18
(Scheme 4). Compound 18 was treated with potassium thio-
Results and Discussion
Our first objective was to identify a synthetic route to racemic
compound 1 via 23 and 24. We prepared 3-(1,3-dioxolan-2-
yl)benzaldehyde (15)5 and 3-hydroxymethylbenzaldehyde (17)6
from 1-bromo-3-(1,3-dioxolan-2-yl)benzene (4) as the starting
material. Compound 4 was converted by formylation conditions
(n-BuLi, THF, then DMF, ¹78 °C) and purified by distillation

S. Kawazoe et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
129
O
O
1) NaBH4
O
n-BuLi, THF, −78 °C
Br
O
O
MeOH
then DMF
y. 58%
15
4
O
2) 3M HCl(aq)
O
HO
O
OH
MeOH
y. 66%
17
16
Scheme 3.
O
O
1) AcSK, DMF
OMe
OMe
Br
HS
2) 1M NaOH(aq)
50% THF-MeOH
y. 88%
18
10
Scheme 4.
acetate in DMF, then hydrolyzed by sodium hydroxide in 50%
THF-MeOH. The crude product was distilled under reduced
pressure to give the thiol 107 in 88% yield.
to afford amine 3, which was also sulfonated with 13 and
purified with chromatography to afford 22 in 58% yield. Acetal
1,3-dioxolane was hydrolyzed with hydrochloric acid in THF
to give the same compound 23 quantitatively (condition D,
Scheme 5).
As a third synthesis pathway, we tried to introduce the
chloroquinolyl unit to benzaldehyde 24 before reduction of the
nitro group. Removing the 1,3-dioxolane protection of com-
pound 20 was successful under the influence of hydrochloric
acid in THF to afford nitrobenzaldehyde 24. The condensa-
tion reaction between 24 and 7-chloroquinaldine (25) did not
proceed to give quinolylvinyl compound 26 with acetic
anhydride in general conditions,11b so this route was suspended
(Scheme 6).
The final stage of synthesis of racemic 1 is described
in Scheme 7. The conditions of the condensation reaction
between benzaldehyde 23 and 7-chloroquinaldine (25) are
shown in Table 1.11 In the general condition of acetic anhydride
in refluxing xylene, trace spots were detected on the TLC
(Entry 1).11b,11c By heating with ZnCl2 in DMF, condensation
proceeded in 15% isolated yield (Entry 2).11a After treatment
in an azeotropic condition with both benzaldehyde 23 and n-
butylamine, the imine was substituted with 25 in the refluxing
acetic acid to give compound 27 in 71% yield (Entry 3). The
condensation product was only detected as a trace spot in acetic
acid, which was the background condition of Entry 3 (Entry 4).
The previous imine formation was effective in condensing
23 with 25. The methyl ester was hydrolyzed with NaOH in
the MeOH and THF, and the mixture was neutralized with an
aqueous solution of citric acid to afford compound 1 in 82%
yield. As described, we identified two synthetic routes from
benzaldehyde 15 and 17 to racemic 1.
We then tried to construct a phenylnitroethyl sulfide skeleton
from the benzaldehyde moiety. The first trial of the condensa-
tion treatment between benzaldehyde 17 or 15, nitromethane,
and thiol 10 all at once (NH4Cl, K2CO3, EtOH, 50-60 °C) gave
phenylnitroethyl sulfide 19 or 20 in modest yield, although
purification of these products with silica gel column chroma-
tography was still required to remove impurities (condition A,
Scheme 5).8 We then attempted to form phenylnitroethyl
sulfide via β-nitrostyrene in a stepwise process.9 Benzaldehyde
15 in benzene was treated with n-butylamine under azeotropic
conditions to give the corresponding imine. After solvent
substitution from benzene to acetic acid, nitromethane was
added to the mixture and heated (80 °C, 2 h), and then thiol 10
was added to give nitro sulfide 19 in 83% yield after puri-
fication with silica gel chromatography. Nitro sulfide 19 was
reduced with Zn in acetic acid and MeOH to afford the corre-
sponding amine 2 quantitatively. Amine 2 was sulfonated with
4-chlorobenzenesulfonyl chloride (13) and crystallized from 2-
propanol/n-hexane to afford 21 in 94% yield. The benzyl
alcohol 21 was treated with MnO2 to give aldehyde 23 in 51%
yield after silica gel chromatography purification (condition C,
Scheme 5).
Benzaldehyde 15 was also transformed into nitro sulfide
20 in the same manner (condition B, Scheme 5). We then
attempted to reduce nitro sulfide 20 to the corresponding amine
3. Reduction by CuBH4 in MeOH proved unsuccessful,10 and
so, using Fe in HCl(aq), the 1,3-dioxolane protecting group
of aldehyde was removed. The reduction of nitro sulfide 20
then proceeded successfully with Zn in acetic acid and MeOH

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Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
Thromboxane A2 and Leukotriene D4 Receptor Antagonists
O
OMe
O
S
OMe
R
O
condition A
nitromethane, 10
NH4Cl, K2CO3
EtOH, 50-60 °C
HO
17 R =
15 R =
S
Zn, AcOH
NH2
R
NO2
HO
R
O
MeOH
50 °C
O
condition B
n-butylamine, benzene
azeotopic
2
3
R =
HO
O
19 R =
20 R =
O
then
O
O
OMe
AcOH,nitromethane
then
R =
HS
O
10, 80 °C
10
O
S
OMe
condition C
MnO2
1,2-dichloroethane
RT, 15 h
O
S
OMe
4-ClC6H4SO2Cl (13)
Cl
Et3N
H
N
S
R
ClCH2CH2Cl or CHCl3
RT, 4 h
O
O
Cl
H
condition D
1M HCl(aq)
THF
N
S
O
O
O
21 R =
22 R =
HO
RT, 1 h
O
23
O
Scheme 5.
O
S
OMe
NO2
O
OMe
O
S
OMe
NO2
Cl
N
25
1M HCl
THF
O
S
NO2
O
Ac2O, xylene
reflux, 4 days
O
Cl
N
20
26
24
Scheme 6.
For the second objective toward synthesis of optically active
1, resolution of amine intermediate 2 with several organic acids
was investigated. Amine 2 was treated with di-p-toluoyl-D-
tartaric acid [(+)-DITOTA] in MeCN/H2O = 10/1 (v/v) to
give crystalline 2a as resolved salt (82% ee) in 24% yield
(Scheme 8 and Table 2, Entry 1). Then recrystallization from
observed (Entry 2). With a reduced amount of (+)-DITOTA,
isolated yield was decreased and the enantiomer ratio increased
(Entries 3-6). After tuning solvent volume, we found that 0.75
molar equivalents of (+)-DITOTA and MeCN/H2O = 12/0.8
(v/v) were appropriate conditions to give the salt (94% ee)
in 31% yield (Entry 7). Only one cycle of recrystallization
was necessary to afford optically pure 2a. Enantiomer 2b was
prepared from 2 and di-p-toluoyl-L-tartaric acid [(¹)-DITOTA]
in the same manner.
25
MeCN/H2O afforded optically pure 2a [>99% ee, ½ꢀꢀD +181
(c 1.00, MeOH)] in 14% yield. We therefore selected
(+)-DITOTA and refined conditions by altering the ratio of
(+)-DITOTA to MeCN/H2O and solvent volumes. When
the rate of MeCN/H2O was 15:1, optical resolution was not
Both salts 2a and 2b were neutralized to give the corre-
sponding free amine 2a and 2b with NaOH(aq), which were

S. Kawazoe et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
131
O
OMe
O
S
OMe
Cl
N
25
Cl
Cl
S
H
H
N
S
N
S
Cl
N
O
O
O
O
O
27
23
O
S
OH
NaOH(aq)
Cl
H
N
MeOH, THF
S
Cl
N
O
O
racemic -1
Scheme 7.
25
Table 1. Condensation between 7-Chloroquinaldine (25)
and Benzaldehyde 23
[½ꢀꢀD +120 (c 0.500, DMSO)] was lower than that of
25
the hydroxymethyl route [½ꢀꢀD +124 (c 0.500, DMSO)] and
required salt formation and three or more cycles of recrystal-
lization to obtain the enantiopure dioxorane amine salt 3a. The
1,3-dioxolane route required fewer reaction steps than the
hydroxymethyl route, but the hydroxymethyl route was more
efficient with respect to resolution of the amines (Scheme 10).
The last stage of the synthetic study of 1 was to achieve an
optically active and scalable synthetic method. Intermediates of
the hydroxymethyl amine 2 from 3-(1,3-dioxolan-2-yl)benz-
aldehyde (15) are oils. Therefore, we tried a telescopic work-
up approach to avoid isolation (Schemes 8 and 11). After the
reduction of compound 15, water and 3 M HCl(aq) were added
to hydrolyze the acetal moiety to give compound 17, which
was extracted, and the solvent was exchanged. This solu-
tion was treated with n-butylamine in the azeotropic condition
and subsequently combined with AcOH and nitromethane.
After generation of nitorostyrene 28, thiol 10 was added to the
mixture and washed with 3 M hydrochloric acid to remove n-
butylamine, achieving one-pot transformation from compound
17 to 19. The nitro sulfide 19 was reduced to amine 2 and
resolved in the same manner. Synthesis of salt 2a from com-
pound 15 was carried out without chromatography purification,
resulting in 18% yield.
Finally, we attempted the above procedure without isolation
of 21a, because isolation required the recovery of a large
amount of the loss of 21a from the mother liquor of the 1st
crop. After the free amine 2a was sulfonated, the reaction
was quenched with water, and compound 21a was extracted.
Solvent was then exchanged to that of the next oxidation
reaction to avoid loss due to isolation. After oxidation of the
alcohol with MnO2, the waste solid, including the oxidizing
agent, was filtered off. The solvent of the filtrate containing
compound 23a was exchanged to operate the next condensation
Entry Conditions
Isolated yield
1
2
3
Ac2O, xylene, reflux
tracea)
15%
71%
ZnCl2, DMF, reflux
n-BuNH2, benzene, reflux, then AcOH,
reflux, 7 h
4
AcOH, reflux
tracea)
a) Thin-layer chromatography (TLC).
then 4-chlorophenylsulfonated to give compound 21a in 58%
yield and 21b in 79% yield (Scheme 9), respectively, includ-
ing the second crop of crystals. Through treatment in the same
manner as the racemate, 21a and 21b were converted to 27a
(60% yield) and 27b (68% yield), respectively, after which the
25
methyl esters were removed to afford compound (+)-1 [½ꢀꢀD
+124 (c 0.500, DMSO), mp 234-237 °C] in 85% yield and
25
compound (¹)-1 [½ꢀꢀD ¹124 (c 0.500, DMSO) mp 234-
238 °C] in 91% yield, respectively.
1,3-Dioxolanamine 3 also crystallized with di-p-toluoyl-D-
tartaric acid in 1,4-dioxane to afford enantioriched amine 3a.
After two cycles of recrystallization, 3a was carried to the next
step. Salt 3a was neutralized to give the corresponding free
amine of 3a with NaHCO3(aq). This amine was reacted with
4-chlorobenzenesulfonyl chloride (13) to give compound 22a,
which was treated under acidic conditions to hydrolyze the
dioxolane acetal to corresponding aldehyde 23a. After treat-
ment in the same manner as racemate 1, compound 23a was
converted to 27a (59% yield). The hydrolysis of the methyl
ester afforded compound (+)-1 in 86% yield, and the 1,3-
dioxolane route showed 6.6% overall yield from 15 through
(+)-1. The enantioriched 1,3-dioxolane-protected route was
accomplished, but the optical purity of the 1,3-dioxolane route

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Thromboxane A2 and Leukotriene D4 Receptor Antagonists
2) 3M HCl(aq)
O
O
1) NaBH4
O
HO
MeOH
O
O
O
OH
MeOH
3) solvent exchange
17
16
15
O
6)
O
S
OMe
NO2
OMe
4) n-BuNH2
toluene
HS
azeotropic condition
concentration
10
NO2
HO
5) nitromethane
AcOH
HO
7) concentration
EtOAc, HCl(aq) wash
solvent exchange
28
19
O
S
OMe
NH2
O
OMe
NH2
8) Zn
4M HCl/ 1,4-dioxane
MeOH
10) (+)-DITOTA
MeCN(aq)
S
11) recryst.
MeCN(aq)
9) filtration, concentration
EtOAc, NaOH(aq)
filtration, seperation
solvent exchange
HO
HO
(+)-DITOTA
2a : (+)-DITOTA salt
y. 18%
2
Scheme 8.
Table 2. Optical Resolution of Compound 2a)
O
OMe
O
S
OMe
NH2
(+)-DITOTA
S
(+)-DITOTA
NH2
HO
HO
2
2a
(+)-DITOTA
/mol
Isolated yield
from 2/%
ee
/%
Entry
Solvent (v/v)
1
2
3
4
5
6
7
8
1.0
1.0
MeCN/H2O = 10/1
MeCN/H2O = 15/1
MeCN/H2O = 15/1
MeCN/H2O = 15/1
MeCN/H2O = 15/1
MeCN/H2O = 15/1
MeCN/H2O = 12/0.8
MeCN/H2O = 9/0.6
24
76
56
29
26
10
31
38
82
not observed
0.80
0.75
0.70
0.60
0.75
0.75
33
94
94
96
94
56
25
a) HPLC: Chiralcel OD-H, n-hexane/EtOH/Et2NH = 85/15/0.1, (+)-DITOTA salt 22a ½ꢀꢀD +181
25
(c 1.00, MeOH), (¹)-DITOTA salt 22b ½ꢀꢀD ¹181 (c 1.00, MeOH).
with 7-chloroquinaldine (25) to give compound 27a (>99%
ee), and then the ester was hydrolyzed (Scheme 9). Therefore,
from 2a through compound (+)-1, chromatography-free oper-
ations were carried out in 68% yield. This pathway showed
12.2% overall yield from 15 through (+)-1 (Scheme 11).
Conclusion
We attempted to identify an alternative approach to the
optically active synthesis for 4-{[(2-{4-chlorophenylsulfonyl-
amino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-

S. Kawazoe et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
133
Cl
2)
O
S
OMe
Cl
S
O
S
OMe
NH2
O
O
Et3N
1,2-dichloroethane
1) EtOAc, 1M NaOH(aq)
concentration
Cl
H
N
S
HO
3) water, CHCl3 extract
concentration
O
O
HO
(+)-DiTOTA
/(-)-DITOTA
21a: from 2a
21b: from 2b
2a: (+)-DITOTA salt
2b: (-)-DITOTA salt
O
S
OMe
1) n-BuNH2
benzene
azeotropic condition
concentration
4) MnO2
1,2-dichloroethane
Cl
H
2)
5) filtration
concentration
N
S
O
O
O
Cl
N
25
AcOH, reflux
23a: from 2a
23b: from 2b
O
S
OMe
O
S
OH
1M NaOH(aq)
THF, MeOH
Cl
Cl
H
H
N
N
S
Cl
N
S
Cl
N
O
O
O
O
27a: from 2a
27b: from 2b
(+)-1a: y.68% from 2a
(-)-1b: from 2b
Scheme 9.
thio]methyl}benzoic acid (1). Optical resolution was accom-
plished in the synthetic route and all isolated intermediates
were easily purified without chromatography. Further optimi-
zation for the asymmetric preparation of 1 is underway.
analyzer and a Yokogawa IC 7000S Ion Chromatoanalyzer.
Optical rotations were measured on a Horiba SEPA-200 polar-
imeter. Chromatographic separations were performed on a
silica gel column using Wakogel C-200 or Merck Silica gel
60 (0.040-0.063 mm). Analytical thin-layer chromatography
(TLC) was carried out on glass plates precoated with Merck
Experimental
General. Melting points were determined using a Yanaco
micro melting apparatus and are uncorrected. Proton nuclear
magnetic resonance (1H NMR) spectra were obtained in CDCl3
or dimethyl sulfoxide-d6 (DMSO-d6) with a JEOL JNM-
EX400, JNM-GX500, or JNM-A500 spectrometer. Chemical
shifts are recorded in parts per million (¤), downfield relative
to tetramethylsilane as an internal standard with coupling con-
stants (J) reported in hertz (Hz). Splitting patterns are desig-
nated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad. Mass spectra (MS) were recorded on a JMS-DX300
or a Hitachi M-80 mass spectrometer. Elementary analyses
were carried out on a Yanaco MT-3 or a Yanaco MT-5 CHN
silica gel 60 F254.
3-(1,3-Dioxolan-2-yl)benzaldehyde (15). To a stirred and
cooled (¹78 °C) solution of 1-bromo-3-(1,3-dioxolan-2-yl)-
benzene (4) (27.07 g, 118 mmol) in THF (270 mL) was added
1.6 M n-BuLi/n-hexane (77.5 mL, 124 mmol) at between ¹58
and ¹78 °C, and the mixture was stirred for 30 min. DMF
(25.5 mL, 355 mmol) was added dropwise at between ¹78 and
¹52 °C. After being stirred for 1.5 h, the mixture was treated
with saturated NH4Cl(aq) and extracted with EtOAc. The
organic phase was washed with brine and dried with MgSO4.
Solvents were removed under reduced pressure. The residue
was distilled under reduced pressure (1 mmHg, 121-124 °C

134
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
Thromboxane A2 and Leukotriene D4 Receptor Antagonists
O
S
OMe
NH2
O
OMe
1) salt formation
(+)-DITOTA
EtOH, 1,4-dioxane
O
O
O
O
S
O
NH2
O
2) recryst. (2 times)
y. 13% (from 15)
O
15
(+)-DITOTA
3
3a
O
OMe
1) NaHCO3(aq)
EtOAc
(+)-1a
y. 51% (from 3a)
Cl
2) 4-ClC6H4SO2Cl (13)
Et3N, ClCH2CH2Cl
0 °C, 20 min
S
O
H
N
S
O
O
O
overall yield: 6.6% (from 15)
22a
Scheme 10.
O
OMe
O
O
O
S
(+)-1a
NH2
HO
(+)-DITOTA
15
2a
overall yield: 12.2% (from 15)
Scheme 11.
fraction) to give 15 (12.1 g, 67.9 mmol, 57.5% yield). 1H NMR
(CDCl3, 90 MHz): ¤ 4.02-4.19 (4H, m), 5.88 (1H, s), 7.45-8.01
(4H, m), 10.04 (1H, s).
1.5 h, the mixture was treated with water (1500 mL) and
extracted with diethyl ether (800 mL). The organic layer was
washed with brine and dried with MgSO4. Solvents were
removed under reduced pressure to give 94.54 g residue as a
brown solid. The residue was dissolved with THF (400 mL)
and MeOH (400 mL) and cooled (in an ice-water bath), and
then 1 M NaOH(aq) (426 mL, 0.426 mmol) was added. After
stirring for 30 min, 1 M HCl(aq) was added, and the mixture
was separated. The aqueous phase was then added with brine,
and the mixture was extracted with diethyl ether. The collected
organic layer was washed with brine and concentrated under
reduced pressure, and the residue was distilled under pressure
(1 mmHg, 120-125 °C fraction) to give 10 (66.5 g, 0.365 mmol,
87.5% yield) as a pale yellow oil. 1H NMR (CDCl3, 90 MHz): ¤
1.79 (1H, t, J = 7.7 Hz), 3.75 (2H, d, J = 7.7 Hz), 3.89 (3H, s),
7.37 (2H, d, J = 8.1 Hz), 7.98 (2H, d, J = 8.1 Hz); GC-MS
(m/z) = 182 (M+).
3-Hydroxymethylbenzaldehyde (17).
To a stirred and
cooled (in an ice-water bath) solution of 3-(1,3-dioxolan-2-
yl)benzaldehyde (15) (685 mg, 3.84 mmol) in MeOH (6.9
mL) was added NaBH4 (73 mg, 1.93 mmol). After stirring for
2 h, water (2 mL) was added and MeOH was removed under
reduced pressure. The residue was treated with water (20 mL)
and EtOAc (20 mL), and the organic layer was separated and
washed with brine and dried with MgSO4. Solvents were
removed under reduced pressure. The residue, 635 mg, was
diluted with MeOH (6 mL) and 1 M HCl(aq) (6 mL) at room
temperature. After being stirred for 2 h, the reaction mixture
was diluted with brine and extracted with EtOAc twice. The
mixed organic layer was washed with brine and dried with
MgSO4. Solvents were removed under reduced pressure. The
residue was purified via silica gel column chromatography (n-
hexane/EtOAc = 3/2) to afford 17 (345 mg, 2.53 mmol, 65.9%
yield). 1H NMR (CDCl3, 90 MHz): ¤ 3.04 (1H, br s), 4.73 (2H,
s), 7.38-7.84 (4H, m), 9.94 (1H, s), EI (m/z) = 136 (M+).
Methyl 4-Sulfanylmethylbenzoate (10). To a stirred and
cooled (in an ice-water bath) solution of 4-methoxycarbonyl-
benzyl bromide (18) (95.6 g, 0.417 mmol) in DMF (400 mL)
was added AcSK (52.4 g, 0.459 mmol). After being stirred for
Methyl
thio}methyl)benzoate (19).
4-({[1-(3-Hydroxymethylphenyl)-2-nitroethyl]-
To a stirred solution of 3-
hydroxymethylbenzaldehyde (17) (7.30 g, 53.6 mmol) in ben-
zene (73 mL), n-butylamine (7.84 g, 107 mmol) was added, and
the mixture was refluxed. After stirring for 1 h in the azeotropic
condition, the mixture was concentrated under reduced pres-
sure. The residue (10.1 g) and nitromethane (5.81 mL, 107
mmol) in acetic acid (70 mL) were heated to 80 °C. After being

S. Kawazoe et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
135
stirred for 2 h, methyl 4-sulfanylmethylbenzoate (10) (10.5 g,
53.6 mmol) was added and stirred for 0.5 h at 80 °C. The
reaction mixture was concentrated and the residue was treated
with water and extracted with EtOAc. The organic layer was
washed with brine and dried with MgSO4. Solvents were
removed under reduced pressure, and the residue was purified
with silica gel chromatography (n-hexane:EtOAc = 1:1) to
give 19 (16.0 g, 44.3 mmol, 82.5% yield) as a pale yellow oil.
1H NMR (CDCl3, 400 MHz): ¤ 3.62 (1H, d, J = 13.6 Hz), 3.71
(1H, d, J = 13.6 Hz), 3.92 (3H, s), 4.40 (1H, dd, J = 6.8,
8.4 Hz), 4.63-4.72 (4H, m), 7.15-7.35 (6H, m), 7.97 (2H, d,
J = 8.0 Hz); MS-FAB (m/z) = 362 (M+ + 1).
Methyl 4-({[2-Amino-1-(3-hydroxymethylphenyl)ethyl]-
thio}methyl)benzoate (2). To a solution of methyl 4-({[1-
(3-hydroxymethylphenyl)-2-nitroethyl]thio}methyl)benzoate
(19) (2.42 g, 6.70 mmol) in MeOH (24 mL) and acetic acid (5.0
mL), zinc powder (4.78 g, 73.1 mmol) was added and heated
to 50 °C. After being stirred for 4 h, the mixture was filtered,
and the filtrate was concentrated under reduced pressure.
After the residue was treated with EtOAc and 1 M NaOH(aq),
the mixture was filtered to remove insoluble solids. The filtrate
was separated and extracted with EtOAc. The organic layer
was washed with brine and dried with MgSO4. Solvents were
removed under reduced pressure to give 2 (2.16 g, 6.52 mmol,
97.3% yield) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz):
¤ 1.81 (3H, br s), 2.97 (2H, dd, J = 2.0, 7.2 Hz), 3.50 (1H, d,
J = 13.6 Hz), 3.59-3.65 (2H, m), 3.91 (3H, s), 4.66 (2H, s),
7.17 (1H, d, J = 7.6 Hz), 7.24-7.34 (5H, m), 7.94 (2H, d, J =
8.8 Hz); MS-FAB (m/z) = 332 (M+ + 1).
3.66 (1H, d, J = 13.6 Hz), 3.78 (1H, t, J = 7.2 Hz), 3.93 (3H, s),
4.71 (1H, t, J = 6.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.38-7.50
(4H, m), 7.61 (1H, br s), 7.66 (2H, d, J = 8.8 Hz), 7.78 (2H, d,
J = 8.0 Hz), 7.95 (2H, d, J = 8.4 Hz), 9.96 (1H, s); MS-FAB
(m/z) = 504 (M+ + 1).
Methyl 4-{[(2-{4-Chlorophenylsulfonylamino}-1-{3-[(E)-
2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}ben-
zoate (27).
To a stirred solution of methyl 4-({[2-(4-
chlorosulfonyl-amino)-1-(3-formylphenyl)ethyl]thio}methyl)-
benzoate (23) (963 mg, 1.91 mmol) in benzene (50 mL), n-
butylamine (201 mg, 2.75 mmol) was added, and the mixture
was refluxed. After being stirred for 1 h under azeotropic con-
ditions, the mixture was concentrated under reduced pressure.
The residue (1.45 g) and 7-chloroquinaldine 356 mg (2.00
mmol) in acetic acid (30 mL) were refluxed, and after being
stirred for 7 h, the mixture was concentrated under reduced
pressure, diluted with water, and extracted with EtOAc. The
organic layer was then washed with 1 M NaOH(aq) and brine
and dried with MgSO4. Solvents were removed under reduced
pressure, and the residue was crystallized from MeCN. The
precipitate was filtered to give 27 (904 mg, 1.36 mmol, 71.2%
yield) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz):
¤ 3.28-3.42 (2H, m), 3.54 (1H, d, J = 14.0 Hz), 3.66 (1H, d,
J = 14.0 Hz), 3.72 (1H, t, J = 7.2 Hz), 3.91 (3H, s), 4.82 (1H, t,
J = 6.4 Hz), 7.06 (1H, d, J = 8.0 Hz), 7.23-7.34 (5H, m), 7.40-
7.48 (3H, m), 7.52 (1H, d, J = 8.0 Hz), 7.59-7.69 (4H, m), 7.73
(1H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.4 Hz), 8.07 (1H, br s),
8.13 (1H, d, J = 8.8 Hz); MS-FAB (m/z) = 663 (M+ + 1).
4-{[(2-{4-Chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-
chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic
Acid (1). To a stirred suspension of methyl 4-{[(2-{4-chloro-
phenylsulfonylamino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)-
vinyl]phenyl}ethyl)thio]methyl}benzoate (27) (545 mg, 0.821
mmol) in THF (5.5 mL) and MeOH (5.5 mL) was added 1 M
NaOH(aq) (2.05 mL), and the mixture was then heated. After
being stirred for 4.5 h at 50 °C, the mixture was added to 10%
aqueous citiric acid (30 mL) and extracted with EtOAc. The
organic layer was washed with brine and dried with MgSO4.
Solvents were removed under reduced pressure. The residue
was crystallized from MeCN. The precipitate was filtered and
washed with EtOAc and MeCN to give 1 (438 mg, 0.674 mmol,
82.1% yield) as pale brown crystals. 1H NMR (DMSO-d6,
400 MHz): ¤ 3.24-3.40 (2H, m), 3.68 (1H, d, J = 14.0 Hz),
3.80 (1H, d, J = 14.0 Hz), 3.86 (1H, t, J = 8.0 Hz), 7.15-8.04
(19H, m), 8.42 (1H, d, J = 8.4 Hz), 12.91 (1H, br s); MS-FAB
(m/z) = 649 (M+ + 1), Anal. Calcd for C33H26N2S2O4Cl2
(649.64): C, 61.01; H, 4.03; N, 4.31; S, 9.87; Cl, 10.91%.
Found: C, 60.95; H, 3.81; N, 4.33; S, 9.97; Cl, 11.11%. Mp
189-192 °C.
Methyl 4-({[2-(4-Chlorophenylsulfonylamino)-1-(3-hy-
droxymethylphenyl)ethyl]thio}methyl)benzoate (21).
To
stirred and cooled (ice-water) solution of methyl 4-({[2-amino-
1-(3-hydroxymethylphenyl)ethyl]thio}methyl)benzoate (2)
(2.02 g, 6.09 mmol) in 1,2-dicholoroethane (40 mL) was added
Et3N (934 ¯L, 6.70 mmol) and 4-chlorobenzensulfonyl chloride
(1.29 g, 6.11 mmol). After being stirred for 4 h at room tem-
perature, the mixture was diluted with water, separated, and
extracted with CHCl3. The organic layer was washed with brine
and dried with MgSO4. Solvents were removed under reduced
pressure, and the residue was crystallized from 2-propanol and
n-hexane. The precipitate was filtered to give 21 (2.90 g, 5.73
1
mmol, 94.1% yield) as a white solid. H NMR (CDCl3, 400
MHz): ¤ 1.95 (1H, br s), 3.23-3.37 (2H, m), 3.52 (1H, d,
J = 13.6 Hz), 3.61-3.75 (2H, m), 3.93 (3H, s), 4.64 (2H, d,
J = 5.2 Hz), 4.81 (1H, t, J = 6.4 Hz), 7.02 (1H, d, J = 6.8
Hz), 7.10 (1H, s), 7.22-7.31 (4H, m), 7.41 (2H, d, J = 8.8 Hz),
7.65 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.4 Hz); MS-FAB
(m/z) = 488 (M+ ¹ 17).
Methyl 4-({[2-(4-Chlorophenylsulfonylamino)-1-(3-form-
ylphenyl)ethyl]thio}methyl)benzoate (23). To a stirring solu-
tion of methyl 4-({[2-(4-chlorophenylsulfonylamino)-1-(3-hy-
droxymethyl-phenyl)ethyl]thio}methyl)benzoate (21) (2.82 g,
5.57 mmol) in 1,2-dichloroethane (56 mL) was added MnO2
(28.2 g). After being stirred for 15 h at room temperature, the
mixture was filtered with celite, and the filtrate was concentrated
under reduced pressure. The residue was purified with silica gel
chromatography (n-hexane/EtOAc = 3/2) to give 23 (1.42 g,
Methyl
4-[({1-[3-(1,3-Dioxolan-2-yl)phenyl]-2-nitro-
ethyl}thio)methyl]benzoate (20). To a stirred solution of
3-(1,3-dioxolan-2-yl)benzaldehyde (15) (500 mg, 2.81 mmol)
in EtOH (10 mL) was added nitromethane (152 ¯L, 2.81 mmol),
methylamine hydrochloride (19 mg, 0.28 mmol), potassium
carbonate (8 mg, 0.06 mmol), and methyl 4-sulfanylmethyl-
benzoate (10) (2.77 g, 14.1 mmol), and then the mixture was
heated to 60 °C. After being stirred for 5 h, the mixture was
concentrated under reduced pressure. The residue was treated
with water and EtOAc (20 mL), and the organic layer was
1
2.82 mmol, 50.6% yield) as a colorless oil. H NMR (CDCl3,
400 MHz): ¤ 3.33 (2H, t, J = 6.8 Hz), 3.53 (1H, d, J = 13.6 Hz),

136
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
Thromboxane A2 and Leukotriene D4 Receptor Antagonists
separated and washed with brine and dried with NaSO4.
Solvents were removed under reduced pressure, and the residue
was purified with silica gel chromatography (n-hexane/
EtOAc = 4/1) to give 20 (638 mg, 1.58 mmol, 56.2% yield)
(1H, br s), 7.66 (1H, d, J = 8.0 Hz), 7.78 (2H, d, J = 7.6 Hz),
7.95 (2H, d, J = 8.4 Hz), 9.97 (1H, s); MS-FAB (m/z) = 502
(M ¹ 1).
¹
Methyl
(+)-4-({[2-Amino-1-(3-hydroxymethylphenyl)-
1
as a colorless oil. H NMR (CDCl3, 400 MHz): ¤ 3.58 (1H, d,
ethyl]thio}methyl)benzoate (+)-Di-p-toluoyl-D-tartrate (2a).
The mixture of methyl («)-4-({[2-amino-1-(3-hydroxymethyl-
phenyl)ethyl]thio}methyl)benzoate (2) (2.19 g, 6.61 mmol) and
(+)-di-p-toluoyl-D-tartaric acid (2.55 g, 6.60 mmol) in MeCN
(44 mL) and water (4.4 mL) was heated to clear the solution
and cooled to room temperature. After being stirred for 1 h, the
slurry was filtered to give 1.53 g colorless crystals. The mixture
of the crystals, MeCN (15 mL), and water (4.6 mL) was heated
to clear the solution, and MeCN (15.6 mL) was added, then
cooled to room temperature. After being stirred for 1 h, the
slurry was filtered and dried to give 2a (664 mg, 0.925 mmol,
J = 14.0 Hz), 3.68 (1H, d, J = 14.0 Hz), 3.92 (3H, s), 4.01-
4.15 (4H, m), 4.41 (1H, t, J = 8.0 Hz), 4.62-4.72 (2H, m),
5.78 (1H, s), 7.24-7.45 (6H, m), 7.97-8.00 (2H, m); MS-FAB
(m/z) = 404 (M+ + 1).
Methyl
4-[({2-Amino-1-[3-(1,3-dioxolan-2-yl)phenyl]-
ethyl}thio)methyl]benzoate (3). To a solution of methyl 4-
[({1-[3-(1,3-dioxolan-2-yl)phenyl]-2-nitroethyl}thio)methyl]-
benzoate (20) (100 mg, 0.25 mmol) in MeOH (5.0 mL) and
acetic acid (1.0 mL), zinc powder 162 mg (2.5 mmol) was
added and heated to 50 °C. After being stirred for 1 h, the
mixture was filtered with celite and washed with MeOH. The
filtrate was treated with saturated NaHCO3(aq), and the mixture
was concentrated under reduced pressure. The residue was
treated with brine and extracted with EtOAc. The organic layer
was separated and extracted with EtOAc and then dried with
NaSO4. Solvents were removed under reduced pressure to give
3 (91 mg, 0.24 mmol, 96% yield) as a pale brown oil. 1H NMR
(CDCl3, 400 MHz): ¤ 3.02 (2H, d, J = 6.8 Hz), 3.48 (1H, d,
J = 13.6 Hz), 3.60 (1H, d, J = 13.6 Hz), 3.65 (1H, t, J = 6.8
Hz), 3.91 (3H, s), 4.03-4.14 (4H, m), 5.79 (1H, s), 7.28-7.42
(6H, m), 7.95 (2H, d, J = 8.0 Hz); MS-FAB (m/z) = 374
(M+ + 1).
1
14.0% yield) as a colorless crystal. H NMR (DMSO-d6, 400
MHz): ¤ 2.34 (6H, s), 3.24 (2H, d, J = 7.6 Hz), 3.62-3.99 (6H,
m), 4.50 (2H, s), 5.60 (2H, s), 7.13-7.40 (10H, m), 7.78-7.90
(6H, m); MS-FAB (m/z) = 332 (M+ + 1), Anal. Calcd for
C18H21NO3S C20H18O8 0.5H2O: C, 62.80; H, 5.55; N, 1.93; S,
25
4.41%. Found: C, 63.07; H, 5.35; N, 1.84; S, 4.21%. ½ꢀꢀD
+180 (c 1.00, MeOH), CHIRALCEL OD-H 250 mm © 4.6
i.d., eluent: Hex/EtOH/Et2NH = 85/15/0.1, temp: 25 °C flow
rate 0.8 mL min¹1. 254 nm >99%ee (¹)-RT 15.1 min. (+)-RT
17.9 min.
Methyl (+)- or (¹)-4-({[2-(4-Chlorophenylsulfonyl-
amino)-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)ben-
zoate (21a). To a stirring suspension of methyl (+)-4-({[2-
amino-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)benzoate
(+)-di-p-toluoyl-D-tartaric acid salt (2a) (864 mg, 1.20 mmol)
in EtOAc was added 1 M NaOH(aq) (2.64 mmol). The organic
layer was separated and washed with brine and dried with
MgSO4, and the solvents were removed under reduced pres-
sure. The residue (373 mg) was diluted in 1,2-dichloroethane
(11 mL) and cooled (in an ice-water bath), and then trieth-
ylamine (173 ¯L, 1.32 mmol) and 4-chlorobenzenesulfonyl
chloride (238 mg, 1.20 mmol) were added. After being stirred
for 0.5 h at room temperature, the mixture was treated with
water. The mixture was separated and extracted with CHCl3.
The collected organic layer was washed with brine and dried
with MgSO4. The solvent was removed under reduced pres-
sure. The residue was triturated in 2-propanol and n-hexane
and filtered to give 21a (209 mg, 0.413 mmol, 34.4% yield).
1H NMR (CDCl3, 400 MHz): ¤ 3.23-3.36 (2H, m), 3.52 (1H, d,
J = 14.0 Hz), 3.62-3.74 (2H, m), 3.93 (3H, s), 4.60-4.66 (3H,
m), 7.01-7.04 (1H, m), 7.09 (1H, s), 7.22-7.32 (4H, m), 7.40
(2H, d, J = 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J =
8.4 Hz); MS-FAB (m/z) = 488 (M+ ¹ 17). To the filtrate was
added diisopropyl ether, and the mixture was filtered to give
Methyl 4-[({2-(4-Chlorophenylsulfonylamino)-1-[3-(1,3-
dioxolan-2-yl)phenyl]ethyl}thio)methyl]benzoate (22). To
a stirred solution of methyl 4-[({2-amino-1-[3-(1,3-dioxolan-2-
yl)phenyl]ethyl}thio)methyl]benzoate (3) (90 mg, 0.24 mmol)
in chloroform (3 mL) was added 4-chlorobenzenesulfonyl
chloride (13) (76 mg, 0.36 mmol) and triethylamine (100 ¯L,
0.72 mmol). After stirring 1 h at ambient temperature, water
1 mL and saturated NaHCO3(aq) were added to the reaction
mixture. The mixture was separated and extracted with CHCl3,
and the organic layer was washed with brine and dried with
Na2SO4. Solvents were then removed under reduced pressure,
and the residue was purified with silica gel chromatography
(n-hexane:EtOAc = 4:1) to give 22 (74 mg, 0.14 mmol, 58%
1
yield) as a colorless oil. H NMR (CDCl3, 400 MHz): ¤ 3.24-
3.37 (2H, m), 3.48 (1H, d, J = 14.4 Hz), 3.60-3.68 (2H, m),
3.94 (3H, s), 4.03-4.16 (4H, m), 4.60 (1H, t, J = 6.0 Hz), 5.73
(1H, s), 7.00-7.42 (8H, m), 7.64 (2H, d, J = 8.4 Hz), 7.96 (2H,
d, J = 8.4 Hz); MS-FAB (m/z) = 548 (M+ + 1).
Methyl 4-({[2-(4-Chlorophenylsulfonylamino)-1-(3-form-
ylphenyl)ethyl]thio}methyl)benzoate (23).
To a stirring
solution of 4-[({2-[4-chlorophenylsulfonylamino]-1-[3-(1,3-di-
oxolan-2-yl)phenyl]ethyl}thio)methyl]benzoate (22) (72 mg,
0.13 mmol) in tetrahydrofuran (10 mL) was added 1 M HCl(aq)
(1 mL), and the mixture was then stirred at ambient temper-
ature. After being stirred for 1 h, the mixture was concentrated.
The residue was treated with water and extracted with ethyl
ether, and the organic layer was washed with brine and dried
with Na2SO4 and concentrated to give 23 (65 mg, 0.13 mmol,
1
21a (143 mg, 0.283 mmol, 23.6% yield) as a solid. H NMR
(CDCl3, 400 MHz): ¤ 3.24-3.37 (2H, m), 3.52 (1H, d, J =
14.0 Hz), 3.62-3.70 (2H, m), 3.93 (3H, s), 4.61-4.66 (3H, m),
7.01-7.04 (1H, m), 7.09 (1H, s), 7.22-7.32 (4H, m), 7.40 (2H,
d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.4
Hz); MS-FAB (m/z) = 488 (M+ ¹ 17).
1
100% yield) as a colorless oil. H NMR (CDCl3, 400 MHz): ¤
Methyl (+)- or (¹)-4-{[(2-{4-Chlorophenylsulfonyl-
amino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}eth-
3.33 (2H, t, J = 6.8 Hz), 3.53 (1H, d, J = 13.6 Hz), 3.66 (1H, d,
J = 13.6 Hz), 3.78 (1H, t, J = 7.2 Hz), 3.94 (3H, s), 4.64 (1H, t,
J = 6.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.38-7.52 (4H, m), 7.61
yl)thio]methyl}benzoate (27a).
To a stirring solution of
methyl (+) or (¹)-4-({[2-(4-chlorophenylsulfonylamino)-1-(3-

S. Kawazoe et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
137
25
hydroxymethylphenyl)ethyl]thio}methyl)benzoate (21a) (340
mg, 0.672 mmol) in 1,2-dichloroethane (17 mL) was added
MnO2 (6.8 g). After being stirred for 8 h at room temperature,
the mixture was filtered through celite. The filtrate was con-
centrated under reduced pressure. To the residue 341 mg in
benzene, n-butylamine (99 mg, 1.35 mmol) was added, and the
mixture was refluxed. After stirring for 0.5 h in the azeotropic
condition, the mixture was concentrated under reduced pres-
sure. The residue and 7-chloroquinaldine (119 mg, 0.670 mmol)
in acetic acid were refluxed. After being stirred for 3 h, the
mixture was concentrated under reduced pressure, and the
residue was diluted with water and 1 M NaOH(aq) and then
extracted with EtOAc. The organic layer was washed with
brine and dried with MgSO4, and the solvent was removed
under reduced pressure. The residue was then crystallized from
MeCN (15 mL), and the precipitate was filtered to give 27a
(262 mg, 0.395 mmol, 58.8% yield) as a pale yellow solid.
1H NMR (CDCl3, 400 MHz): ¤ 3.28-3.42 (2H, m), 3.54 (1H, d,
J = 13.6 Hz), 3.66 (1H, d, J = 13.6 Hz), 3.72 (1H, t, J = 7.2
Hz), 3.91 (3H, s), 4.82 (1H, br s), 7.06 (1H, d, J = 8.0 Hz),
7.23-7.34 (5H, m), 7.40-7.47 (3H, m), 7.52 (1H, d, J = 7.6
Hz), 7.60-7.68 (4H, m), 7.73 (1H, d, J = 8.8 Hz), 7.96 (2H, d,
J = 8.4 Hz), 8.06 (1H, d, J = 2.0 Hz), 8.12 (1H, d, J = 8.4 Hz);
MS-FAB (m/z) = 663 (M+ + 1).
Found: C, 63.32; H, 5.66; N, 1.98; S, 4.46; ½ꢀꢀD ¹184 (c 1.00,
MeOH), CHIRALCEL OD-H 250 mm © 4.6 I.D., eluent:
Hex/EtOH/Et2NH = 85/15/0.1, temp: 25 °C flow rate 0.8
mL min¹1. 254 nm >99%ee (¹)-RT 15.1 min. (+)-RT 17.9 min.
Methyl (+)- or (¹)-4-({[2-(4-Chlorophenylsulfonyl-
amino)-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)ben-
zoate (21b). To a stirring suspension of methyl (¹)-4-({[2-
amino-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)benzoate
(¹)-di-p-toluoyl-L-tartrate (2b) (950 mg, 1.32 mmol) in EtOAc
was added 1 M NaOH(aq). The organic layer was separated
and washed with brine and dried with MgSO4. The solvents
were removed under reduced pressure. The residue (470 mg)
was diluted in 1,2-dichloroethane (15 mL) and cooled (in an
ice-water bath), after which triethylamine (203 ¯L, 1.45 mmol)
and 4-chlorobenzenesulfonyl chloride (279 mg, 1.32 mmol)
were added. After being stirred for 0.5 h at room temperature,
the mixture was treated with water and then separated and
extracted with CHCl3. The collected organic layer was washed
with brine and dried with MgSO4, and the solvents were
removed under reduced pressure. The residue was triturated in
2-propanol, n-hexane, and diisopropyl ether and then filtered to
give 21b (525 mg, 1.04 mmol, 78.8% yield) as a colorless solid.
1H NMR (CDCl3, 400 MHz): ¤ 2.12 (1H, br s), 3.23-3.36 (2H,
m), 3.52 (1H, d, J = 14.0 Hz), 3.61-3.74 (2H, m), 3.92 (3H, s),
4.62 (2H, d, J = 4.8 Hz), 4.94 (1H, t, J = 6.4 Hz), 7.01 (1H, d,
J = 5.6 Hz), 7.10 (1H, s), 7.22-7.31 (4H, m), 7.40 (2H, d, J =
8.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.94 (2H, d, J = 8.0 Hz);
(+)-4-{[(2-{4-Chlorophenylsulfonylamino}-1-{3-[(E)-2-
(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}ben-
zoic Acid (1a). To a stirring suspension of methyl (+) or
(¹)-4-{[(2-{4-chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-
chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoate
(27a) (250 mg, 0.377 mmol) in THF (2.5 mL) and MeOH
(2.5 mL) was added 1 M NaOH(aq) (0.94 mL), and the mixture
was then heated. After stirring for 4 h at 60 °C, 10% aqueous
citric acid was added to the mixture, and the mixture was
then extracted with EtOAc. The organic layer was washed with
brine and dried with MgSO4. Solvent was removed under
reduced pressure. The residue in MeCN was heated to crys-
tallize and then cooled to room temperature. The slurry was
filtered to give 1a (209 mg, 0.322 mmol, 85.4% yield) as pale
yellow solid. 1H NMR (DMSO-d6, 400 MHz): ¤ 3.24-3.32 (2H,
m), 3.68 (1H, d, J = 13.6 Hz), 3.80 (1H, d, J = 13.6 Hz), 3.83-
3.88 (1H, m), 7.15-8.04 (19H, m), 8.42 (1H, d, J = 8.4 Hz),
12.91 (1H, br s); MS-FAB (m/z) = 649 (M+ + 1), Anal. Calcd
for C33H26N2S2O4Cl2: C, 61.01; H, 4.03; N, 4.31; S, 9.87;
Cl, 10.91%. Found: C, 60.73; H, 3.89; N, 4.23; S, 9.71; Cl,
¹
MS-FAB (m/z) = 504 (M ¹ 1).
Methyl (+)- or (¹)-4-{[(2-{4-Chlorophenylsulfonyl-
amino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}eth-
yl)thio]methyl}benzoate (27b).
To a stirring solution of
methyl (+) or (¹)-4-({[2-(4-chlorophenylsulfonylamino)-1-(3-
hydroxymethylphenyl)ethyl]thio}methyl)benzoate (21b) (425
mg, 0.840 mmol) in 1,2-dichloroethane (21 mL) was added
MnO2 (8.5 g). After stirring for 3 h at room temperature, the
mixture was filtered through celite. The filtrate was concen-
trated under reduced pressure. To the residue of 433 mg in ben-
zene, n-butylamine (123 mg, 1.68 mmol) was added, and the
mixture was refluxed. After stirring for 0.5 h under azeotropic
conditions, the mixture was concentrated under reduced
pressure. The residue and 7-chloroquinaldine (149 mg, 0.839
mmol) in acetic acid were refluxed. After stirring for 4 h, the
mixture was concentrated under reduced pressure, and the
residue was diluted with water and 1 M NaOH(aq) then
extracted with EtOAc. The organic layer was washed with
brine and dried with MgSO4. Solvent was removed under
reduced pressure. The residue was crystallized from MeCN (15
mL). The precipitate was filtered to give 27b (381 mg, 0.574
25
10.84%. ½ꢀꢀD +124 (c 0.500, DMSO), mp 234-237 °C.
Methyl
(¹)-4-({[2-Amino-1-(3-hydroxymethylphenyl)-
ethyl]thio}methyl)benzoate (¹)-di-p-toluoyl-L-tartrate (2b).
To a solution of methyl («)-4-({[2-amino-1-(3-hydroxymeth-
ylphenyl)ethyl]thio}methyl)benzoate (2) (3.06 g, 9.23 mmol) in
MeCN (60 mL) and water (6 mL) was added (¹)-di-p-toluoyl-L-
tartaric acid 3.57 g (9.23 mmol). After being stirred for 1 h
at room temperature, the slurry was filtered to give 2.97 g
colorless crystals. The crystals were recrystallized from MeCN
(45 mL) and water (7.5 mL) to give 2b (1.38 g, 1.92 mmol,
1
mmol, 68.3% yield) as a pale yellow solid. H NMR (CDCl3,
400 MHz): ¤ 3.28-3.42 (2H, m), 3.54 (1H, d, J = 13.6 Hz),
3.66 (1H, d, J = 13.6 Hz), 3.72 (1H, t, J = 7.2 Hz), 3.91 (3H,
s), 4.83 (1H, t, J = 6.4 Hz), 7.06 (1H, d, J = 8.4 Hz), 7.23-7.34
(5H, m), 7.40-7.48 (3H, m), 7.52 (1H, d, J = 8.0 Hz), 7.59-
7.69 (4H, m), 7.73 (1H, d, J = 8.8 Hz), 7.97 (2H, d, J =
8.4 Hz), 8.06 (1H, d, J = 2.0 Hz), 8.12 (1H, d, J = 8.8 Hz);
MS-FAB (m/z) = 663 (M+ + 1).
(¹)-4-{[(2-{4-Chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-
chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic
Acid (1b). To a stirring suspension of methyl (¹) or (+)-4-
1
20.8% yield) as a colorless crystal. H NMR (DMSO-d6, 400
MHz): ¤ 2.34 (6H, s), 3.24 (2H, d, J = 7.6 Hz), 3.62-3.99 (6H,
m), 4.49 (2H, s), 5.59 (2H, s), 7.13-7.40 (10H, m), 7.78-7.90
(6H, m); MS-FAB (m/z) = 332 (M+ + 1), Anal. Calcd for
C18H21NSO3 C20H18O8: C, 63.59; H, 5.48; N, 1.95; S, 4.47;

138
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
Thromboxane A2 and Leukotriene D4 Receptor Antagonists
{[(2-{4-chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-chloro-2-
quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoate (27b) (250
mg, 0.377 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was
added 1 M NaOH(aq) (0.94 mL), and the mixture was then
heated. After stirring for 5 h at 60 °C, 10% aqueous citric acid
was added to the mixture, which was then extracted with
EtOAc. The organic layer was washed with brine and dried
with MgSO4, and solvents were removed under reduced
pressure. The residue in MeCN was heated to crystallize then
cooled to room temperature, and the slurry was filtered to give
1b (222 mg, 0.341 mmol, 90.5% yield) as a pale yellow solid.
1H NMR (DMSO-d6, 400 MHz): ¤ 3.24-3.32 (2H, m), 3.68
(1H, d, J = 13.6 Hz), 3.80 (1H, d, J = 13.6 Hz), 3.87 (1H, t,
J = 8.0 Hz), 7.15-8.04 (19H, m), 8.42 (1H, d, J = 8.4 Hz),
12.88 (1H, br s); MS-FAB (m/z) = 649 (M+ + 1), Anal. Calcd
for C33H26N2S2O4Cl2 0.3H2O: C, 60.51; H, 4.09; N, 4.28; S,
9.79; Cl, 10.82%. Found: C, 60.26; H, 3.81; N, 4.27; S, 10.11;
5.63 (2H, s), 5.69 (1H, s), 7.26-7.39 (10H, m), 7.80-7.89 (6H,
m); MS-FAB (m/z) = 374 (M+ + 1), Anal. Calcd for C20H23-
NO4S C20H18O8 0.5H2O: C, 62.49; H, 5.51; N, 1.82; S, 4.17%.
Found: C, 62.14; H, 5.53; N, 1.73; S, 4.04%.
Synthesis of (+)-1a via 3a. Methyl (+)- or (¹)-4-{[(2-
{4-Chlorophenylsulfonylamino}-1-{3-[(E)-2-(7-chloro-2-
quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoate (27a).
To a stirring suspension of methyl (+)- or (¹)-4-[({2-amino-
1-[3-(1,3-dioxolan-2-yl)phenyl]ethyl}thio)methyl]benzoate
(+)-di-p-toluoyl-D-tartrate (3a) (1.80 g, 2.37 mmol) in EtOAc
was added sat NaHCO3(aq) (2.64 mmol). The organic layer
was separated and washed with brine before being dried with
Na2SO4. The solvents were removed under reduced pressure,
and the residue was diluted in 1,2-dichloroethane (10 mL) and
cooled (in an ice-water bath), then mixed with triethylamine
(660 ¯L, 4.74 mmol) and 4-chlorobenzenesulfonyl chloride
(600 mg, 2.84 mmol). After being stirred for 20 min at room
temperature, the mixture was treated with 1 M HCl(aq) (10 mL)
before being separated and extracted with CHCl3. The collected
organic layer was washed with sat NaHCO3(aq) and brine and
dried with Na2SO4. Solvents were removed under reduced
pressure to give 23a (1.50 g) as a pale yellow oil. To the
residue in benzene, n-butylamine (347 mg, 4.74 mmol) was
added, and the mixture was refluxed. After being stirred for 1 h
under azeotropic conditions, the mixture was concentrated
under reduced pressure. The residue and 7-chloroquinaldine
(463 mg, 2.61 mmol) in acetic acid (20 mL) were refluxed.
After being stirred for 18 h, the mixture was concentrated under
reduced pressure, and the residue was diluted with water and
sat NaHCO3(aq), then extracted with EtOAc. The organic layer
was washed with brine and dried with Na2SO4. Solvents were
removed under reduced pressure. The residue was crystallized
from MeCN and diisopropyl ether. The precipitate was filtered
to give 27a (924 mg, 1.39 mmol, 58.6% yield) as a pale yellow
25
Cl, 11.09%. ½ꢀꢀD ¹124 (c 0.500, DMSO), mp 234-238 °C.
Synthesis of (+)-1a via 3a. Methyl (+)- or (¹)-4-[({2-
Amino-1-[3-(1,3-dioxolan-2-yl)phenyl]ethyl}thio)methyl]-
benzoate (+)-Di-p-toluoyl-D-tartrate (3a). To a stirred solu-
tion of 3-(1,3-dioxolan-2-yl)benzaldehyde (15) (3.56 g, 20.0
mmol) in benzene (50 mL), n-butylamine (2.92 g, 40.0 mmol)
was added, and the mixture was refluxed. After stirring for
1 h under azeotropic conditions, the mixture was concentrated
under reduced pressure. The residue and nitromethane (2.44
mL, 40 mmol) in acetic acid (50 mL) were heated at 60 °C.
After stirring for 3 h, the mixture was mixed with methyl 4-
sulfanylmethylbenzoate (10) (3.64 g, 20.0 mmol) and stirred
for 12 h at 60 °C, then heated to 80 °C and stirred for 4 h. The
reaction mixture was concentrated and the residue treated with
saturated NaHCO3(aq) and extracted with EtOAc. The organic
layer was then washed with brine and dried with Na2SO4, and
solvents were removed under reduced pressure to afford 8.71 g
residue as a brown oil. To a stirring and cooled (in an ice-water
bath) solution of the residue 8.71 g in MeOH (100 mL) and
AcOH (20 mL), zinc powder (13.08 g, 200 mmol) was added,
and the mixture was heated to 50 °C. After being stirred for
2 h, the mixture was filtered and washed with MeOH, and the
solvents were concentrated under reduced pressure. After the
residue was treated with saturated NaHCO3(aq) and extracted
with CHCl3. The organic layer was washed with water, washed
with brine, and dried with Na2SO4. Solvents were removed
under reduced pressure. To a solution of the residue (8.92 g)
in 1,4-dioxane (45 mL) was added (+)-di-p-toluoyl-D-tartaric
acid monohydrate (16.18 g, 20.0 mmol) then heated to clear
the solution. After stirring for 8 h at room temperature, the
slurry was filtered and dried to give colorless crystals (3.59 g).
The mixture of the crystals (3.50 g), EtOH (8.75 mL) and 1,4-
dioxane (8.75 mL) were heated to clear the solution, after
which it was cooled to room temperature. After 12 h, the crys-
tals were filtered and dried to give colorless crystals (2.47 g).
The mixture of the crystals (2.40 g), EtOH (6.0 mL), and 1,4-
dioxane (6.0 mL) was heated to clear the solution and cooled
to room temperature. After 12 h, the crystals were filtered and
dried to give 3a (1.957 g, 2.58 mmol, 12.9% yield) as colorless
1
solid. H NMR (CDCl3, 400 MHz): ¤ 3.28-3.42 (2H, m), 3.55
(1H, d, J = 13.6 Hz), 3.64-3.74 (2H, m), 3.91 (3H, s), 4.69
(1H, br t), 7.06-7.34 (6H, m), 7.40-7.47 (3H, m), 7.52-7.68
(5H, m), 7.74 (1H, d, J = 8.8 Hz), 7.97 (2H, d, J = 8.0 Hz),
8.08 (1H, d, J = 2.0 Hz), 8.13 (1H, d, J = 8.8 Hz); MS-FAB
¹
(m/z) = 661 (M ¹ 1).
Synthesis of (+)-1a via 3a. (+)-4-{[(2-{4-Chlorophenyl-
sulfonylamino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phen-
yl}ethyl)thio]methyl}benzoic Acid (1a). To a stirring sus-
pension of methyl (+)- or (¹)-4-{[(2-{4-chlorophenylsulfonyl-
amino}-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)-
thio]methyl}banzoate (27a) (900 mg, 1.36 mmol) in THF (8.0
mL) and MeOH (4.0 mL) was added 1 M NaOH(aq) (8.0 mL)
then heated. After stirring for 2 h at 50 °C, the mixture was
added to 10% aqueous citric acid and then extracted with
EtOAc. The organic layer was washed with brine and dried
with Na2SO4. Solvents were removed under reduced pressure.
The residue was treated in MeCN to crystallize and then stirred
for 2 h at room temperature. The slurry was filtered and washed
with MeCN and diethyl ether to give 1a (758 mg, 1.17 mmol,
86.0% yield). 1H NMR (DMSO-d6, 400 MHz): ¤ 3.23-3.32
(2H, m), 3.68 (1H, d, J = 13.6 Hz), 3.80 (1H, d, J = 13.6 Hz),
3.84-3.89 (1H, m), 7.15-8.04 (19H, m), 8.42 (1H, d, J =
1
crystals. H NMR (DMSO-d6, 400 MHz): ¤ 2.34 (6H, s), 3.24
¹
(2H, d, J = 7.2 Hz), 3.57 (3H, s), 3.64 (1H, d, J = 13.2 Hz),
3.80 (2H, d, J = 13.2 Hz), 3.85 (2H, s), 3.93-4.08 (4H, m),
8.4 Hz), 12.91 (1H, s); MS-FAB (m/z) = 647 (M ¹ 1), 649
(M+ + 1), Anal. Calcd for C33H26N2S2O4Cl2: C, 61.01; H,

S. Kawazoe et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 1 (2014)
139
4.03; N, 4.31; S, 9.87; Cl, 10.91%. Found: C, 60.87; H, 4.12;
N, 4.32; S, 9.80; Cl, 10.87%. ½ꢀꢀD 120 (c 0.500, DMSO).
1 h at room temperature, the mixture was treated with water
and then separated and extracted with CHCl3. The collected
organic layer was washed with brine and dried with MgSO4.
The solvents were removed under reduced pressure. To a
stirring solution of the residue 3.02 g in 1,2-dichloroethane
(85 mL) was added MnO2 (56 g). After being stirred for 6 h
at room temperature, the mixture was filtered through celite.
The filtrate was concentrated under reduced pressure. To the
residue (2.86 g) in benzene, n-butylamine (1.11 g, 11.2 mmol)
was added, and the mixture was refluxed. After stirring for 1 h
in the azeotropic condition, the mixture was concentrated under
reduced pressure. The residue and 7-chloroquinaldine 997 mg
(5.61 mmol) in acetic acid (40 mL) were refluxed. After being
stirred for 5 h, the mixture was concentrated under reduced
pressure, and the residue was diluted with water and 1 M
NaOH(aq) then extracted with EtOAc. The organic layer was
washed with brine and dried with MgSO4. Solvents were
removed under reduced pressure, and the residue was crystal-
lized from MeCN (45 mL). The precipitate was then filtered to
give 2.68 g as pale yellow crystals [CHIRALCEL OD-H 250
mm © 4.6 i.d., eluent: Hex/EtOH/Et2NH = 85/15/0.1, temp:
25 °C flow rate 0.8 mL min¹1. 254 nm >99%ee RT 30.5 min.
RT 39.2 min.]. To a stirring suspension of the crystals (2.68 g)
in THF (25 mL) and MeOH (25 mL) was added 1 M NaOH(aq)
(10.1 mL), and the mixture as then heated. After stirring for
5 h at 60 °C, 10% aqueous citric acid was then added to the
mixture, and the mixture was extracted with EtOAc. The
organic layer was washed with brine and dried with MgSO4.
Solvents were removed under reduced pressure. The residue in
MeCN was heated to crystallize and then cooled to room tem-
perature. The slurry was filtered to give (+)-1a (2.47 g, 3.80
25
Demonstration of Chromatography Free Synthesis of
(+)-1a. To a stirred and cooled (in an ice-water bath) solution
of 3-(1,3-dioxolan-2-yl)benzaldehyde (15) (12.1 g, 67.9 mmol)
in MeOH (120 mL) was added NaBH4 1.28 g (33.8 mmol).
After being stirred for 1 h, water (60 mL) and 3 M HCl(aq)
(60 mL) was added and then further stirred for 1 h at room
temperature. The organic solvents were removed under reduced
pressure. The residue was extracted with CHCl3, and the
organic layer was washed with brine and dried with MgSO4.
Solvents were removed under reduced pressure. To the residue
(9.16 g) in toluene (92 mL), n-buthylamine (13.3 mL, 135
mmol) was added, and the mixture was refluxed. After being
stirred for 1.5 h in the azeotropic condition, the mixture was
cooled to 80 °C and mixed with acetic acid (45 mL) and
nitromethane (5.47 mL, 101 mmol). After being stirred for 2 h
at 80 °C, the mixture was mixed with methyl 4-sulfanyl-
methylbenzoate (10) (12.5 g, 63.7 mmol). After being stirred
for 1 h at 80 °C, the reaction mixture was concentrated under
reduced pressure, and the residue was treated with 1 M HCl(aq)
(300 mL) and extracted with EtOAc (300 mL). The organic
layer was washed with brine and dried with MgSO4. Solvents
were removed under reduced pressure. To a stirring and cooled
(in an ice-water bath) solution of the residue (27.8 g) in MeOH
(240 mL) and 4 M HCl/1,4-dioxane (73 mL), zinc powder
(44 g, 0.67 mol) was added, and the mixture was then heated
at 60 °C. After being stirred for 6 h, the mixture was filtered,
and the filtrate was concentrated under reduced pressure. After
the residue was treated with EtOAc and 1 M NaOH(aq) (400
mL) and 3 M NaOH(aq) (100 mL), the mixture was filtered to
remove insoluble solids. The filtrate was separated. The organic
layer was washed with brine and dried with MgSO4. Solvents
were removed under reduced pressure. To a solution of the
residue (23.7 g) in MeCN (200 mL) and water (13.4 mL) was
added (+)-di-p-toluoyl-D-tartaric acid (18.2 g, 47.1 mmol).
After being stirred overnight at room temperature, the slurry
was filtered to give colorless crystals (12.9 g). The mixture of
the crystals, MeCN (51.6 mL) and water (10.3 mL) were heated
to clear the solution and added MeCN (103 mL), then cooled
to room temperature. The resulting slurry was filtered and
dried to give 2a (8.83 g, 12.3 mmol, 18.1% yield) as colorless
1
mmol, 67.9% yield) as a pale yellow solid. H NMR (DMSO-
d6, 400 MHz): ¤ 3.23-3.35 (2H, m), 3.68 (1H, d, J = 14.0
Hz), 3.80 (1H, d, J = 14.0 Hz), 3.85-3.89 (1H, m), 7.16-8.04
(19H, m), 8.42 (1H, d, J = 8.4 Hz), 12.91 (1H, br s); MS-FAB
(m/z) = 649 (M+), Anal. Calcd for C33H26N2S2O4Cl2: C,
61.01; H, 4.03; N, 4.31; S, 9.87; Cl, 10.91%. Found: C, 60.75;
H, 3.99; N, 4.38; S, 10.05; Cl, 11.17%.
The authors would like to thank the staff of the analytical
department for elemental analysis and spectral measurements.
Supporting Information
1
crystals. H NMR (DMSO-d6, 400 MHz): ¤ 2.34 (6H, s), 3.24
(2H, d, J = 7.6 Hz), 3.62-3.99 (6H, m), 4.49 (2H, s), 5.61 (2H,
s), 7.13-7.40 (10H, m), 7.79-7.90 (6H, m); MS-FAB (m/z) =
332 (M+ + 1), Anal. Calcd for C18H21NO3S C20H18O8: C,
63.59; H, 5.48; N, 1.95; S, 4.47%. Found: C, 63.46; H, 5.37;
N, 1.96; S, 4.57%. CHIRALCEL OD-H 250 mm © 4.6 i.d.,
eluent: Hex/EtOH/Et2NH = 85/15/0.1, temp: 25 °C flow rate
0.8 mL min¹1. 254 nm >92%ee (¹)-RT 15.1 min. (+)-RT
17.9 min.
To a stirring suspension of 2a (4.02 g, 5.60 mmol) in EtOAc
(40 mL) was added 1 M NaOH(aq) (40 mL). The organic
layer was separated and washed with brine and dried with
MgSO4. The solvents were removed under reduced pressure.
The residue (2.05 g) was diluted in 1,2-dichloroethane (60 mL)
and cooled (in an ice-water bath), after which triethylamine
(859 ¯L, 6.16 mmol) and 4-chlorobenzenesulfonyl chloride
(13) (1.18 g, 5.60 mmol) were added. After being stirred for
1H NMR and MS spectral data and chiral HPLC data of 2a,
2b, 21a, and 27a are provided. Figures S1-S35. These mate-
rials are available free of charge on the web at http://www.
csj.jp/journals/bcsj/.
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