Design and synthesis of a selective EP4-receptor agonist. Part 2: 3,7-dithiaPGE1 derivatives with high selectivity

Article abstract of DOI:10.1016/S0968-0896(01)00352-2

To identify new highly selective EP4-agonists, further modification of the 16-phenyl moiety of 1 was continued. 16-(3-Methoxymethyl)phenyl derivatives 13-_6q and 16-(3-ethoxymethyl)phenyl derivatives 13-_7e showed more selectivity and potent agonist activity than 1. 16-(3-Methyl-4-hydroxy)phenyl derivative 18-_14e demonstrated excellent subtype selectivity, while both its receptor affinity and agonist activity were less potent than those of 13-_6q. Structure activity relationships (SARs) are also d scussed. Copyright

Full text of DOI:10.1016/S0968-0896(01)00352-2

Bioorganic & Medicinal Chemistry 10 (2002) 989–1008
Design and Synthesis of a Selective EP4-Receptor Agonist.
Part 2: 3,7-DithiaPGE1 Derivatives with High Selectivity
Toru Maruyama,* Masaki Asada, Tai Shiraishi, Akiharu Ishida, Hideyuki Yoshida,
Takayuki Maruyama, Shuichi Ohuchida, Hisao Nakai, Kigen Kondo
and Masaaki Toda
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan
Received 6 August 2001; accepted 4 October 2001
Abstract—To identify new highly selective EP4-agonists, further modification of the 16-phenyl moiety of 1 was continued. 16-(3-
Methoxymethyl)phenyl derivatives 13-6q and 16-(3-ethoxymethyl)phenyl derivatives 13-7e showed more selectivity and potent ago-
nist activity than 1. 16-(3-Methyl-4-hydroxy)phenyl derivative 18-14e demonstrated excellent subtype selectivity, while both its
receptor affinity and agonist activity were less potent than those of 13-6q. Structure–activity relationships (SARs) are also discussed.
# 2002 Elsevier Science Ltd. All rights reserved.
Chemistry
Introduction
Syntheses of 16-substituted-phenyl-o-tetranor-3,7-dithia
With chemical modification to find highly selective EP4-
receptor agonists, a tremendous amount of the reported
structural information1 should be organized in advance
because of the diversity of chemical modification of the
PG skeleton. First, a series of 3,7-dithiaPGE1 analogues
were discovered in our laboratory as chemical leads for
structurally new EP4-receptor agonists.2 Second, we
focused on chemical modification of their o-chains. In
our preceding paper, we reported identification of 16-
phenyl-o-tetranor-3,7-dithiaPGE1 1 derivatives as new
chemical leads for EP4-receptor agonists. Since one of
the important aims of this project was to identify a
highly selective EP4-receptor agonist to disclose novel
biological roles of the EP4-receptor, the receptor selec-
tivity and agonist activity of 1 should be much more
improved. In this study, we focused our attention on
further improvement of the biological properties in 1 by
chemical modification of its 16-phenyl moiety (Scheme 1).
We describe here the successful modification of 1 to
obtain highly selective EP4-receptor agonists 13-6q,
18-14e and others. Structure–activity relationships
(SARs) are also discussed.
PGE1 analogues are outlined in Scheme 2. To obtain a
variety of analogues, one of the best synthetic methods
included Nozaki–Hiyama coupling reaction3 as a key
step. Conjugate addition4 of (2-tributyltin)vinylcyano-
cuprate, which was prepared from 3, to the chiral enone
2 followed by trapping of the resulting enolate anion
with acetic anhydride afforded the enol acetate 4. The
vinyltin part in 4 was converted to the iodoolefin 5 by
treatment with iodine. Hiyama-coupling of the iodo-
olefin 5 and arylacetaldehyde 6a–q, 7a–k and 8a–m
provided 11–6a–11–8m, respectively. Deprotection of the
TBS groups afforded 12-6a–12-8m as a diastereomeric
mixture, which was separated by Lobar column to give
two diastereoisomers. Compounds 13-6a–13-8m derived
from the corresponding more polar isomers always
exhibited more potent activities than those derived from
the less polar isomers. Based on this finding, the config-
uration of 15-OH of the more polar isomer was tentatively
assigned to the natural configuration.5 Sequential enzy-
matic hydrolysis of 15(S) 12-6a–12-8m: hydrolysis of the
enol ester with AmanoPS followed by hydrolysis of the
methyl ester with PLE afforded 13-6a–13-8m, respectively.
Synthesis of 3,7-dithiaPGE1 analogues possessing mis-
cellaneous o chains are described in Scheme 3. Accord-
ing to the same procedure as described in Scheme 2,
*Corresponding author. Tel.: +81-75-961-1151; fax: +81-75-962-
9314; e-mail: to.maruyama@ono.co.jp
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00352-2

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T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
16-14a–16-15e, which were prepared by Hiyama-coupling
reaction of 5 and miscellaneous aldehydes 14a–k and
15a–e, were converted to 18-14a–18-15e, respectively.
Results and Discussion
To improve the biological profiles of 1 (Scheme 1) as an
EP4-receptor selective agonist, chemical modification
was further continued. It was especially important to
improve KiEP4/KiEP3 subtype selectivity because
removal of the uterine contractile activity, which is
mediated by EP3-receptor, is indispensable to develop
EP4-receptor agonists as clinically useful drugs.
Improvement of the EP4-receptor selectivity and ago-
nist activity by introduction of substituents into the
phenyl moiety of 1 was investigated. Among the com-
pounds tested, two series of 3,7-dithiaPGE1 analogues
possessing 16-(3-alkoxymethyl)phenyl and 16-(3,4-di-
substituted)phenyl analogues were found to be highly
selective EP4-receptor agonists. 3,7-DithiaPGE1 analo-
gues possessing other miscellaneous o-chains as described
in Table 4 were also synthesized and evaluated for their
ability to improve the EP4-receptor selectivity and ago-
nist activity. 16-Thienyl-o-tetranor-PGE1 analogues
18-15cÀe exhibited potent agonist activity among these
analogues but their subtype selectivities were relatively
low.
As described in Table 1, the effects of substituents of the
phenyl moiety in 1 on the EP4-receptor selectivity and
Scheme 1. Optimization of 16-phenyl-o-tetranor-3,7-dithia PGE1
analogues 13-6q and 18-14e
.
Scheme 2. Synthesis of 16-phenyl-o-tetranor-3,7-dithia PGEs 13-6a–13-8m. Reagents: (a) MeLi, CuCN, THF then Ac2O; (b) l2, ether; (c) CrCl2,
NiCl2, DMF; (d) (HF)n-py, pyridine, CH3CN; (e) AmanoPS, DMSO, phosphate buffer then PLE.

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
991
Scheme 3. Synthesis of 3,7-dithiaPGs possessing miscellaneous o chains. Reagents: (a) CrCl2, NiCl2, DMF; (b) (HF)nꢀ py, pyridine CH3CN; (c)
AmanoPS, DMSO, phosphate buffer then PLE.
Table 1. Further optimization of 16-phenylo-tetranor-3,7-dithia PGE1 analogues 13-6a–13-6r
Compound
R
Binding Ki (nM)
EC50 (nM)
mEP1
mEP2mEP3
mEP4
hlP
mEP4
13-6a
13-6b
13-6c
13-6d
13-6e
13-6f
13-6g
13-6h
13-6i
13-6j
13-6k
13-6l
13-6m
13-6n
13-6o
13-6p
13-6q
13-6r
o-Me
m-Me
p-Me
m-Cl
p-Cl
o-OMe
m-OMe
p-OMe
m-OEt
p-OEt
m-SMe
p-SMe
m-OH
>104
>104
>104
630
2500
760
1200
2300
240
140
100
72
21
10
1100
510
22
1.9
7.3
0.8
5.5
32
9.9
7.1
30
24
2.2
9.1
51
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
420
2.8
270
1.7
95
580
37
32
160
86
2.7
52
85
48
N.T.
N.T.
3.1
62
560
>104
>104
3100
>104
>104
1200
>104
2000
>104
>104
>104
>104
>104
2600
>104
1500
1700
2300
1200
1400
5100
>104
>104
>104
2100
8300
220
1500
1400
54
110
460
>104
>104
>104
1200
1200
p-OH
37
m-SO2Me
p-SO2Me
m-CH2OMe
p-CH2OMe
>104
>104
9.7
28
Using membrane fractions of CHO cells expressing the prostanoid receptors, the mouse (m) EP-receptor of human (h) IP-receptor, Ki values were
determined by competitive binding assay, which was performed according to the method of Kiriyama et al. with some modifications.7 With regard to
the subtype-receptor agonist activity, EC50 values were determined based on the effects of the test compounds on the increase in intracellular cAMP
production in EP4-receptor expressing cells. N.T.=Not tested.

992
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
the potency of the agonist activity were investigated.
Introduction of a methyl group provided 13-6a, 13-6b
and 13-6c retaining good EP4-receptor selectivity, while
agonist activities were increased in 13-6b and reduced in
13-6a and 13-6c. Introduction of a methoxy group afforded
13-6f, 13-6g and 13-6h retaining good EP4-receptor
selectivity, while maximal reduction of the agonist
activity was observed in 13-6f. Biological evaluation of
the two series of compounds 13-6aÀc and 13-6fÀh clearly
demonstrated that the meta- and para-isomers are much
more preferred to the ortho-isomers. Based on this find-
ing, meta- and para-isomers were evaluated on a variety
of substituents. Introduction of a chloro group afforded
13-6d and 13-6e with increased and decreased agonist
activity, respectively, although the EP3-receptor affi-
nities of both were increased. Subtype selectivity of 13-6e
was markedly reduced. Introduction of an ethoxy group
provided 13-6i and 13-6j retaining good selectivity, while
their EP4-receptor affinity and agonist activities were
less potent compared with those of 1. Of the derivatives
with a methylthio group, the meta-isomer 13-6k showed
more potent agonist activity retaining selectivity. Phenol
derivatives 13-6m and 13-6n demonstrated increased EP4-
receptor selectivity with less potent agonist activity than
1 while both the Ki and EC50 values were decreased. The
EP4-receptor selectivity of 13-6n was excellent because it
did not exhibit any affinity to other receptors even at
10 mM, but its agonist activity was not potent (48 nM).
meta- and para-Methylsulfonylphenyl derivatives 13-6o
and 13-6p did not show any affinity to any of the receptors
at 10 mM. Introduction of a methoxymethyl group affor-
ded 13-6q and 13-6r retaining good EP4-receptor affinities.
The agonist activity of the meta-isomer 13-6q was excellent.
Among the compounds listed in Table 1, 13-6q exhibited
the best profile as a potent and selective EP4-receptor
agonist and had a markedly weak EC50 value6 (5800 nM)
for its EP3-receptor affinity (Ki=1200 nM). para-Phenol
derivatives 13-6n also demonstrated excellent subtype
selectivity, while both of receptor affinity and agonist
activity were less potent than those of 13-6q.
replacement with an allyl group afforded 13-7g with
excellent EP4-receptor selectivity, although its EC50
value was nearly 4-fold less potent than that of 13-6q.
Replacement of the propyl group in 13-7f with an iso-
propyl group afforded 13-7h with retention of good EP4-
receptor selectivity and agonist activity. The EP4-recep-
tor selectivity of 13-7i with a phenoxymethyl group was
improved relative to 13-6q, while its EC50 value was
nearly 10-fold less potent. Conversion of the methyl
group in 13-6q to a cyclohexyl group provided 13-7i with
good subtype selectivity and a markedly reduced EC50
value. Introduction of a methyl group into the methyl-
ene moiety in 13-6q afforded 13-7k with marked
reduction of EP4-receptor affinity and the EC50 value.
Table 2b shows the effects of the other meta-substituents
in the phenyl moiety of the 16-phenyl-o-tetranor-3,7-
dithiaPGE1 on receptor affinity and the EC50 value.
m-Ethyl derivative 13-8a exhibited moderate EP4-recep-
tor selectivity and potent agonist activity, with a profile
very close to that of the corresponding m-methyl deri-
vative 13-6b. m-Vinyl derivative 13-8b exhibited less EP4-
receptor selectivity to the receptors EP1, EP2, EP3 with
a less potent EC50 values than 13-8a. m-Propyl deriva-
tive 13-8c exhibited reduced selectivity to the EP3-
receptor, while its agonist activity was nearly equivalent
to that of 13-8a. m-Isopropyl derivative 13-8d also
exhibited moderate EP4-receptor selectivity, while its
EC50 value was more than 30-fold less potent than that
of 13-8a. Although the m-benzyl derivative 13-8e showed
increased EP4-receptor selectivity, its EC50 value was
markedly reduced. Both the receptor selectivity and the
EC50 value were improved in m-(2-fluoroethyl) deriva-
tive 13-8f. m-Alkyne derivatives 13-8g and 13-8h demon-
strated potent EP4-receptor affinity with moderate EC50
values, although their subtype selectivities were different
in their affinity to the IP-receptor. m-Phenyl derivative
13-8i also exhibited IP-receptor affinity. The conjugated
phenyl moiety in the meta-position tended to increase
the IP-receptor affinity. The IP-receptor affinity was not
observed in meta-heteroaromatic derivatives 13-8j and
13-8k, both of which exhibited moderate EP4-receptor
selectivity. The EC50 value of 13-8k was 10-fold more
potent than that of 13-8j because of its more hydrophilic
properties due to the oxygen atom contained in the furyl
moiety. m-Cyano derivative 13-8l showed moderate
EP4-receptor selectivity in the binding assay while its
EC50 value was markedly reduced compared with 13-8a.
m-Trifluoro derivative 13-8m exhibited reduced selectiv-
ity because of its increased EP3-receptor affinity, while
its EC50 value and affinity for the EP4-receptor were
potent.
Based on the findings described above, our further
attempts at optimization were focused on introduction
of the meta-substituent (m-) into the phenyl moiety of 1
as described in Table 2a and b. First, fine tuning of the
m-methoxymethyl moiety of 13-6q was carried out.
Although m-hydroxymethyl derivative 13-7a exhibited
good EP4-receptor selectivity and the agonist activity,
the Ki and EC50 values were less potent and almost the
same as those of 1. Replacement of the oxygen atom of
the m-methoxymethyl moiety of 13-6q with a sulfur
atom provided 13-7b with retention of the potent EP4-
receptor affinity and agonist activity and increased EP3-
receptor affinity. One or two carbon homologation of
the methylene moiety of the m-substituent in 13-6q
afforded 13-7c and 13-7d with retention of EP4-receptor
selectivity while their agonist activities were nearly 4-
and 15-fold less potent than that of 13-6q, respectively.
One or two carbon homologation of the methyl group
in the m-methoxymethyl moiety afforded 13-7e and 13-7f
with retention of good EP4-receptor selectivity and
potent agonist activity, respectively. The EC50 value of
13-7e was 4-fold more potent than that of 13-7f. Similar
Biological evaluation of 16-(disubstituted)phenyl deriva-
tives was conducted as shown in Table 3. Structural
hybridization of 13-6b and 13-6n provided 16-(3-methyl-
4-hydroxy)phenyl derivative 18-14e, which demonstrated
excellent EP4-receptor selectivity with moderate agonist
activity. 16-(3,4-Dichloro)phenyl derivative 18-14a
showed increased EP3-receptor affinity in addition to
potent EP4-receptor affinity. 3,4-Dimethoxy, 3-chloro-
4-methoxy and 3-methyl-4-methoxy derivatives 18-14b
18-14c and 18-14d showed the markedly reduced EC50
,

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
993
values, while the EP4-receptor affinity was retained in
18-14c and 18-14d, and markedly reduced in 18-14b. Both
the EP4-receptor selectivity and the EC50 value of
3-chloro-6-methoxy derivative 18-14f and 2,5-dimethyl
derivative 18-14g were markedly reduced. 16-(2,3-Dis-
ubstituted)phenyl derivatives 18-14h and 18-14i also
showed markedly reduced agonist activity with reduced
EP4-receptor affinity. The EP4-receptor affinity and
selectivity of 16-(3,5-disubstituted)phenyl derivatives
18-14j and 18-14k were reduced.
activity, while its subtype selectivity was nearly the same
as that of 1. The profile was almost retained in 16-(2-
thienyl)derivative 18-15d. Introduction of a methox-
ymethyl group into position-5 of the thiophene moiety
of 18-15d produced 18-15e but did not improve on the
biological profile of 1.
Based on the SARs mentioned above, we estimated the
effects of the o chain structure on the subtype selectivity
of 3,7-dithiaPGs as described below. A lipophilic group
on the meta-position of the 16-phenyl moiety in 1
seemed to be indispensable for the potent EP4-receptor
agonist activity as illustrated in Table 1 (13-6b,6d) and
Table 2b (13-8a,8c,8m), although most of these com-
pounds also exhibited high affinity to the EP3-receptor.
A hydrophilic group on the meta- or the para-position
was found to reduce affinity to the EP3-receptor as illu-
strated in Table 1 (13-6g,6h,6m,6n). Based on these obser-
vations, the EP3-receptor was suggested to show affinity
to the lipophilic o chain moiety. This is why introduc-
As shown in Table 4, replacement of the 16-phenyl
moiety in 1 with miscellaneous aromatic groups was
carried out to produce 18-15a–18-15e. 16-Naphthyl deriva-
tive 18-15a demonstrated moderate subtype selectivity
and EP4-receptor affinity, while its EC50 value was 2–3-
fold less than that of 1. A reduced EP4-receptor affinity
was obtained in the structural conversion from 18-15a to
18-15b retaining the EC50 value. 16-(3-Thienyl)derivative
18-15c exhibited potent EP4-receptor affinity and agonist
Table 2. (a) Further optimization of m-substituted of 16-phenyl-o-tetranor-3,7-dithiaPGE1 analogues 13-7a–13-7k
Compound
R
Binding Ki (nM)
mEP2MEP3 mEP4
EC50 (nM)
mEP1
hlP
mEP4
13-7a
13-7b
13-7c
13-7d
13-7e
13-7f
13-7g
13-7h
13-7i
13-7j
13-7k
CH2OH
CH2SMe
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
1900
8500
5300
3100
>104
>104
7700
1300
7400
2700
>104
>104
>104
430
22
6.0
8.5
100
9.4
5.2
1.4
16
4.2
40
130
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
39
4.8
12
44
2.5
10
12
6.7
28
400
500
CH2CH2OMe
CH2CH2CH2OMe
CH2OEt
3000
>104
4500
3000
6200
1600
1900
>104
3800
CH2OPrn
CH2Oallyl
CH2OPri
CH2OPh
CH2Ohexc
CH(CH3)OMe
(b) Effects on the biological activities of the other m-substituents of the 16-phenyl-o-tetranor-3,7-dithiaPGE1analogues 13-8a–13-8m
Compound
R
Binding Ki (nM)
mEP2mEP3 mEP4
EC50 (nM)
mEP1
hlP
mEP4
13-8a
13-8b
13-8c
13-8d
13-8e
13-8f
13-8g
13-8h
13-8i
13-8j
13-8k
13-8l
13-8m
Et
vinyl
1900
760
420
150
270
1600
>104
770
760
550
1100
680
200
5400
1800
120
120
19
2.5
4.2
1.3
7.1
7.1
6.5
6.3
0.34
1.0
2.7
2.8
>104
>104
>104
>104
>104
>104
>104
150
2.0
12
4.8
67
280
3.7
19
12
40
Prn
>104
>104
>104
2800
>104
>104
>104
>104
>104
1400
2000
Pri
CH2Ph
CH2CH2F
96
820
900
200
230
970
1500
250
920
47
Phenyl
2-thienyl
2-furyl
CN
770
>104
>104
>104
>104
42
3.4
110
6.1
30
2.1
CF3

994
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
tion of a hydrophilic group into the phenyl moiety of 1
was predicted to be effective to increase the EP4-recep-
tor selectivity.
1(A). On the basis of the biological data of 13-7c and
13-7d possessing relatively low EP3-receptor affinity, the
position of the ether oxygen atom of the methoxymethyl
moiety was estimated to be important to optimize their
EP4-receptor agonist activity and subtype selectivity.
The sizes of the lipophilic pockets of EP4-receptor were
speculated to be quite limited because the EP4-receptor
affinities and agonist activities of 13-7k and 13-7j were
reduced. As a result, the EP4-receptor selectivity was
markedly improved by introduction of a hydrophilic
oxygen atom into the appropriate position of the phenyl
The analysis described above yielded 18-14e, which was
designed based on the structural hybridization of 13-6b
and 13-6n. The excellent EP4-receptor selectivity of 18-14e
was speculated to be dependent on its proper interaction
with the EP4-receptor as described in Chart 1(B). How-
ever, this interaction seems unlikely in the p-methoxy
derivative 18-14d due to steric repulsion as illustrated in
Chart 1(C) and (D).
moiety, as illustrated in 13-6q and 18-14e
.
A similar interaction was thought to be plausible in the
m-methoxymethyl group of 13-6q as described in Chart
In summary, we have identified highly selective EP4-
receptor agonists 13-6q, 13-7e and 18-14e starting from
Table 3. Biological evaluation of 16-(disubstituted)phenyl-o-tetranor 3,7-dithiaPGE1
Compound
X, Y
Binding Ki (nM)
mEP2mEP3 mEP4
EC50 (nM)
mEP1
hlP
mEP4
18-14a
18-14b
18-14c
18-14d
18-14e
18-14f
18-14g
18-14h
18-14i
18-14j
18-14k
3,4-dichloro
3,4-dimethoxy
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
4700
>104
1200
2700
>104
450
17
4.1
250
11
20
13
37
370
74
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
>104
45
950
110
210
25
290
8400
630
1600
87
>104
2200
6200
>104
900
3-chloro, 4-methoxy
3-methyl, 4-methoxy
3-methyl, 4-hydroxy
3-chloro, 6-methoxy
2,5-dimethyl
2-methoxy, 3-methyl
2,3-dimethyl
3,5-dimethyl
640
2000
>104
870
2000
3300
>104
3100
450
92
13
14
3-methoxy, 5-methyl
1400
42
Table 4. Biological evaluation of 3,7-dithia PGE1 possessing miscellaneous o chains
Compound
R
Binding Ki (nM)
mEP4
EC50 (nM)
100
mEP1
mEP2mEP3
hlP
mEP4
18-15a
>104
>104
320
13
>104
18-15b
18-15c
18-15d
18-15e
>104
960
>104
720
310
36
65
1.9
4.3
13
>104
>104
>104
>104
100
4.4
3.7
23
570
1800
>104
100
240
>104

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
995
stirring for 1 h, 2 (1.84 g, 4.7 mmol) in THF (5 mL) was
added dropwise to the stirred dark yellow solution at
À70 ꢁC. After stirring for 30 min, the reaction mixture
was treated with acetic anhydride (1.8 mL, 18.8 mmol)
and stirred at that temperature for an additional 1 h.
The reaction was quenched with aq NH4Cl/aq NH3, (9/
1) and stirred vigorously for 30 min without cooling.
The orange precipitate was removed by filtration
through a pad of Celite. The aqueous layer was extrac-
ted with hexane and the combined organic layer was
washed with water and brine, dried over Na2SO4. The
solvent was removed by evaporation and the residue
was purified by column chromatography on silica gel
(hexane–EtOAc/hexane, 1/15) to give 4 as a pale yellow
1
oil (3.2g, 89%). H NMR (200 MHz, CDCl3) d 6.14 (d,
J=18 Hz, 1H), 5.82(dd, J=18, 8 Hz, 1H), 4.25–4.15
(m, 1H), 3.72 (s, 3H), 3.21 (s, 2H), 3.25–3.15 (m, 1H),
2.9–2.3 (m, 6H), 2.18 (s, 3H), 1.9–1.7 (m, 2H), 1.6–1.2
(m, 18H), 1.0–0.8 (m, 18H), 0.06 (s, 6H).
Chart 1. Interaction of the o chain moieties with the EP4-receptor.
the detailed structural modification of 1. The agonist
activities of 13-6q and 13-7e were excellent. The EC50
value of 18-14e was nearly 10-fold less potent than the
other two compounds, while its subtype selectivity was
excellent. SAR of the a chain in these compounds will
be discussed in the following paper.
(3S,4R)-1-Acetoxy-4-(t-butyldimethylsiloxy)-3-(trans-2-
iodovinyl)-2-(6-methoxycarbonyl-1,5-dithiahexyl)-1-cyclo-
pentene 5. To a stirred solution of 4 (3.2g, 4.2mmol) in
ether (40 mL) was added iodine (1.07 g, 4.2mmol) at
room temperature. The reaction mixture was stirred for
30 min and then successively washed with saturated
aqueous Na2S2O3, aqueous KF and brine, and dried
over MgSO4. The solvent was removed by evaporation
and the residue was purified by column chromato-
graphy on silica gel (EtOAc/hexane, 1/20) to give 5 as a
pale yellow oil (1.78 g, 73%). 1H NMR (200 MHz,
CDCl3) d 6.45 (dd, J=15, 8 Hz, 1H), 6.29 (d, J=15 Hz,
1H), 4.2–4.1 (m, 1H), 3.72 (s, 3H), 3.22 (s, 2H), 3.25–
3.15 (m, 1H), 2.85 (ddd, J=16, 8, 2Hz, 1H), 2.75–2.60
(m, 4H), 2.47 (ddd, J=16, 5, 2Hz, 1H), 2.18 (s, 3H),
1.82(pent, J=6 Hz, 2H), 0.87 (s,. 9H), 0.04 (s, 6H).
Experimental
General procedures
Analytical samples were homogeneous as confirmed by
TLC, and afforded spectroscopic results consistent with
the assigned structures. Proton nuclear magnetic reso-
nance spectra (1H NMR) were obtained on a Varian
Gemini-200 or VXR-200s spectrometer using deuter-
ated chloroform (CDCl3) or deuterated methanol
(CD3OD) as the solvent. Fast atom bombardment mass
spectra (FAB-MS) and electron ionization (EI) were
obtained on a JEOL JMS-DX303HF spectrometer.
Atmospheric pressure chemical ionization (APCI) was
determined on a Hitachi M1200H spectrometer. Infra-
red spectra (IR) were measured on a Perkin-Elmer FT-
IR 1760Â spectrometer. Melting points and results of
elemental analyses were uncorrected. Column chroma-
tography was carried out on silica gel [Merck silica gel
60 (0.063–0.200 mm), Wako gel C200 or Fuji Silysia
BW235]. Thin layer chromatography was performed on
silica gel (Merck TLC or HPTLC plates, silica gel 60
F254). The following abbreviations for solvents and
reagents are used: tetrahydrofuran (THF), ethyl acetate
(EtOAc), dimethylformamide (DMF), dichloromethane
(CH2Cl2), acetic acid (AcOH).
General procedure for the preparation of 3,7-dithia-16-
Ph-PGE1 derivatives
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(2-
methyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6a. To a stirred light green suspension of chromium(II)
chloride (210 mg, 1.7 mmol) and nickel(II) chloride
(5 mg) in anhydrous DMF (3 mL) was added dropwise a
solution of 5 (200 mg, 0.34 mmol) and an aldehyde
(91 mg, 0.68 mmol) in DMF (1.5 mL) at room tempera-
ture. The resulting dark green solution was stirred for
1 h. The reaction mixture was poured into water, shaken
with ether and the insoluble substances were removed
by filtration through a pad of Celite. The filtrate was
separated and the aqueous layer was extracted with
ether. The combined organic layer was washed with
water and brine, and dried over MgSO4. After removal
of the solvent, the residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1/6–1/
4) to give 11-6a as a pale yellow oil (124 mg, 60%).
1H NMR (200 MHz, CDCl3) d 7.20–6.90 (m, 4H),
5.77 (dd, J=16, 6 Hz, 1H), 5.75 (dd, J=16, 8 Hz,
1H), 5.57 (m, 1H), 4.38 (m, 1H), 4.09 (m, 1H), 3.73 (s,
3H), 3.21 (s, 2H), 3.15 (m, 1H), 2.95–2.4 (m, 8H), 2.33
(s, 3H), 2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.87 (s, 9H), 0.04
(s, 6H).
(3S,4R)-1-Acetoxy-4-(t-butyldimethylsiloxy)-3-(trans-2-tri-
butylstanylvinyl)-2-(6-methoxycarbonyl-1,5-dithiahexyl)-1-
cyclopentene 4. To a stirred suspension of copper(I)
cyanide (636 mg, 7.1 mmol) in freshly distilled dry THF
(10 mL) was slowly added methyllithium (1.03 M in
ether, 13.8 mL, 14.2mmol) at À70 ꢁC under Ar. The
reaction mixture was warmed to 0 ꢁC in 5 min. To the
resulting clear solution was rapidly added a solution of
vinyltin (4.42g, 7.3 mmol) in THF (10 mL). After

996
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6b. 67% yield; H NMR (200 MHz, CDCl3) d 7.20
(m, 1H), 2.18 (s, 3H), 1.88–1.70 (m, 2H), 1.41 (t,
J=7.0 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 6H).
1
(m, 1H), 7.1–6.9 (m, 3H), 5.77 (dd, J=16, 6 Hz, 1H),
5.75 (dd, J=16, 8 Hz, 1H), 5.57 (m, 1H), 4.38 (m, 1H),
4.09 (m, 1H), 3.73 (s, 3H), 3.21 (s, 2H), 3.15 (m, 1H),
2.95–2.4 (m, 8H), 2.33 (s, 3H), 2.19 (s, 3H), 1.9–1.7 (m,
2H), 0.87 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
ethoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6j. 88% yield; H NMR (200 MHz, CDCl3) d 7.14
(d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 5.80–5.50
(m, 2H), 4.37–4.28 (m, 1H), 4.18–3.98 (m, 4H), 3.71 (s,
3H), 3.20 (s, 2H), 3.19–3.10 (m, 1H), 2.92–2.53 (m, 7H),
2.44–2.38 (m, 1H), 2.19 (s, 3H), 1.85–1.70 (m, 2H), 1.40
(t, J=7.0 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
methyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
11-6c. 74% yield; H NMR (200 MHz, CDCl3) d 7.12
(s, 4H), 5.8–5.5 (m, 2H), 4.4–4.3 (m, 1H), 4.2–4.0 (m,
1H), 3.72 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.5
(m, 7H), 2.5–2.4 (m, 1H), 2.19 (s, 3H), 1.9–1.7 (m, 3H),
0.88 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methylthio)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6k. 66% yield; H NMR (200 MHz, CDCl3) d 7.2–
6.95 (m, 4H), 5.75 (dd, J=16, 6 Hz, 1H), 5.73 (dd,
J=16, 6 Hz, 1H), 5.57 (dd, J=15, 8 Hz, 1H), 4.38 (m,
1H), 4.08 (m, 1H), 3.72 (s, 3H), 3.21 (s, 2H), 3.15 (m,
1H), 2.95–2.35 (m, 8H), 2.47 (s, 3H), 2.19 (s, 3H), 1.9–
1.7 (m, 2H), 0.86 (s, 9H), 0.02 (m, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
chloro)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
11-6d. 67% yield; H NMR (200 MHz, CDCl3) d 7.26–
7.07 (m, 4H), 5.73 (dd, J=16, 6 Hz, 1H), 5.71 (dd,
J=16, 6 Hz, 1H), 5.56 (m, 1H), 4.37 (m, 1H), 4.07 (m,
1H), 3.73 (s, 3H), 3.21 (s, 2H), 3.14 (m, 1H), 2.9–2.4 (m,
8H), 2.2 (s, 3H), 2.0–1.8 (m, 3H), 0.87 (s, 9H), 0.04 (s,
3H), 0.03 (s, 3H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
methylthio)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6l. 81% yield; 1H NMR (200 MHz, CDCl3) d 7.4–7.1
(m, 4H), 5.8–5.5 (m, 2H), 4.34 (m, 1H), 4.08 (m, 1H),
3.73 (s, 3H), 3.21 (s, 2H), 3.12 (m, 1H), 2.95–2.35 (m,
8H), 2.46 (s, 3H), 2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.87 (s,
9H), 0.03 (m, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
chloro)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
11-6e. 72% yield; H NMR (200 MHz, CDCl3) d 7.28
(d, J=8 Hz, 2H), 7.17 (d, J=8 Hz, 2H), 5.8–5.5 (m,
2H), 4.4–4.3 (m, 1H), 4.1–4.0 (m, 1H), 3.72 (s, 3H), 3.22
(s, 2H), 3.2–3.1 (m, 1H), 3.0–2.5 (m, 7H), 2.43 (dd,
J=16, 5 Hz, 1H), 2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.88 (s,
9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
hydroxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dieno-
ate 11-6m. 80% yield; H NMR (200 MHz, CDCl3) d
7.22–7.08 (m, 1H), 6.86–6.66 (m, 2H), 5.82–5.67 (m,
1H), 5.56 (dd, J=15.3, 8.1 Hz, 1H), 4.42–4.26 (m, 1H),
4.15–4.04 (m, 1H), 3.73 (s, 3H), 3.24–3.08 (m, 3H),
2.95–2.36 (m, 8H), 2.19 (s, 3H), 1.90–1.52 (m, 2H), 0.97
(s, 9H), 0.86 (s, 9H), 0.18 (s, 6H), 0.05 (s, 3H), 0.02(s,
3H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(2-
methoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
11-6f. 80% yield; H NMR (200 MHz, CDCl3) d 7.33–
6.78 (m, 4H), 5.83–5.67 (m, 1H), 5.64–5.48 (m, 1H),
4.50–4.33 (m, 1H), 4.20–4.02 (m, 1H), 3.83 (s, 3H), 3.72
(s, 2H), 3.24–3.08 (m, 3H), 3.00–2.20 (m, 9H), 2.18 (s,
3H), 1.92–1.72 (m, 2H), 0.86 (s, 9), 0.03 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
hydroxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dieno-
ate 11-6n. 77% yield; 1H NMR (200 MHz, CDCl3) d
7.07 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 5.80–
5.43 (m, 2H), 4.38–4.23 (m, 1H), 4.15–4.04 (m, 1H), 3.73
(s, 3H), 3.21 (s, 2H), 3.19–3.10 (m, 1H), 2.95–2.36 (m,
8H), 2.19 (s, 3H), 1.88–1.64 (m, 2H), 0.97 (s, 9H), 0.87
(s, 9H), 0.18 (s, 6H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6g. Compound 11-6g was used for the next reaction
without further purification.
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
methoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6h. 80% yield; H NMR (200 MHz, CDCl3) d 7.16
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methylsulfonyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-6o. 66% yield; H NMR (200 MHz, CDCl3)
1
1
(d, J=8.2Hz, 2H), 6.84 (d, J=8.2 Hz, 2H), 5.82–5.49
(m, 2H), 4.41–4.26 (m, 1H), 4.17–4.05 (m, 1H), 3.79 (s,
3H), 3.74 (s, 3H), 3.21 (s, 2H), 3.19–3.10 (m, 1H), 2.97–
2.50 (m, 7H), 2.50–2.36 (m, 1H), 2.19 (s, 3H), 1.88–1.68
(m, 2H), 0.84 (s, 9H), 0.02 (s, 6H).
d 7.85–7.78 (m, 2H), 7.60–7.45 (m, 2H), 5.82–5.50 (m,
2H), 4.45–4.37 (m, 1H), 4.17–4.05 (m, 1H), 3.73 (s, 3H),
3.22 (s, 2H), 3.22–3.05 (m, 1H), 3.06 (s, 3H), 2.95–2.38
(m, 8H), 2.19 (s, 3H), 1.88–1.75 (m, 2H), 1.80–1.50 (br,
1H), 0.87 (s, 9H), 0.03 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
ethoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-6i. 91% yield; H NMR (200 MHz, CDCl3) d 7.21–
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
methylsulfonyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-6p. 63% yield; H NMR (200 MHz, CDCl3)
1
1
7.18 (m, 1H), 6.82–6.75 (m, 3H), 5.80–5.53 (m, 2H),
4.41–4.32(m, 1H), 4.17–3.95 (m, 4H), 3.74 (s, 3H), 3.21
(s, 2H), 3.19–3.10 (m, 1H), 2.92–2.55 (m, 7H), 2.50–2.40
d 7.86 (d, 2H, J=8 Hz), 7.45 (d, 2H, J=8 Hz), 5.75 (dd,
J=15, 6 Hz, 1H), 5.58 (dd, J=15, 8 Hz, 1H), 4.42(m,
1H), 4.10 (m, 1H), 3.72 (s, 3H), 3.21 (s, 2H), 3.14 (m,

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
997
1H), 3.04 (s, 3H), 3.0–2.3 (m, 8H), 2.19 (s, 3H), 1.9–1.7
(m, 2H), 0.87 (s, 9H), 0.03 (m, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
propoxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7f. 78% yield; H NMR (200 MHz, CDCl3)
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methoxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-6q. 74% yield; H NMR (200 MHz, CDCl3)
d 7.3–7.1 (m, 4H), 5.8–5.5 (m, 2H), 4.42 (s, 2H), 4.4–
4.3 (m, 1H), 4.15–4.05 (m, 1H), 3.74 (s, 3H), 3.40 (m,
3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.4 (m, 8H),
2.18 (s, 3H), 1.9–1.7 (m, 2H), 0.86 (s, 9H), 0.03 (s,
6H).
d 7.34–7.11 (m, 4H), 5.84–5.51 (m, 2H), 4.49 (s, 2H),
4.38 (m, 1H), 4.10 (m, 1H), 3.73 (s, 3H), 3.44 (t,
J=7 Hz, 2H), 3.21 (s, 2H), 3.16 (m, 1H), 2.95–2.37 (m,
8H), 2.19 (s, 3H), 1.81–1.53 (m, 4H), 0.95 (t, J=7 Hz,
3H), 0.87 (s, 9H), 0.04 (m, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
allyloxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
1
dienoate 11-7g. 77% yield; H NMR (200 MHz, CDCl3)
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(4-
methoxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-6r. 80% yield; H NMR (200 MHz, CDCl3)
d 7.4–7.2 (m, 4H), 5.8–5.5 (m, 2H), 4.42 (s, 2H), 4.5–4.3
(m, 1H), 4.2–4.0 (m, 1H), 3.73 (s, 3H), 3.38 (m, 3H),
3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.4 (m, 8H), 2.21 (s,
3H), 1.9–1.7 (m, 3H), 0.89 (s, 9H), 0.05 (s, 6H).
d 7.43–7.10 (m, 4H), 6.08–5.85 (m, 1H), 5.84–5.68 (m,
1H), 5.57 (dd, J=15.4, 8.4 Hz, 1H), 5.39–5.15 (m, 2H),
4.50 (s, 2H), 4.46–4.30 (m, 1H), 4.19–3.97 (m, 3H), 3.72
(s, 3H), 3.20 (s, 2H), 3.19–3.09 (m, 1H), 2.95–2.37 (m,
8H), 2.19 (s, 3H), 1.92–1.68 (m, 2H), 0.86 (s, 9H), 0.03
(m, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
isopropoxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-
8,13-dienoate 11-7h. 65% yield; 1H NMR (200 MHz,
CDCl3) d 7.3–7.1 (m, 4H), 5.8–5.5 (m, 2H), 4.42 (s, 2H),
4.4–4.3 (m, 1H), 4.15–4.05 (m, 1H), 3.74 (s, 3H), 3.40
(m, 3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.4 (m,
8H), 2.18 (s, 3H), 1.9–1.7 (m, 2H), 0.86 (s, 9H), 0.03
(s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
hydroxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7a. 79% yield; H NMR (200 MHz, CDCl3)
d 7.33–7.05 (m, 4H), 5.76 (dd, J=15, 5.8 Hz, 1H), 5.58
(m, 1H), 4.72(s, 2H), 4.38 (m, 1H), 4.09 (m, 1H), 3.73
(s, 3H), 3.21 (s, 2H), 3.15 (m, 1H), 2.97–2.37 (m, 8H),
2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.94 (s, 9H), 0.87 (s, 9H),
0.06 (1m, 2H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
phenoxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7i. 87% yield; H NMR (200 MHz, CDCl3)
d 7.42–7.14 (m, 6H), 7.03–6.90 (m, 3H), 5.77 (dd, J=15,
5.8 Hz, 1H), 5.58 (dd, J=15, 8.3 Hz, 1H), 5.05 (s, 2H),
4.40 (m, 1H), 4.11 (m, 1H), 3.72 (s, 3H), 3.20 (s, 2H),
3.17 (m, 1H), 2.98–2.37 (m, 8H), 2.19 (s, 3H), 1.9–1.7
(m, 2H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methylthiomethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7b. 90% yield; H NMR (200 MHz, CDCl3)
d 7.40–6.94 (m, 4H), 5.80–5.46 (m, 2H), 4.44–4.30 (m,
1H), 4.20–4.02 (m, 1H), 3.73 (s, 3H), 3.65 (s, 2H), 3.24–
3.10 (m, 3H), 2.98–2.34 (m, 10H), 2.19 (s, 3H), 2.00 (s,
3H), 1.90–1.60 (m, 3H), 0.87 (s, 9H), 0.03 (s, 6H).
1
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methoxyethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7c. 75% yield; H NMR (200 MHz, CDCl3)
d 7.30–7.05 (m, 4H), 5.84–5.50 (m, 2H), 4.41–4.30 (m,
1H), 4.17–4.04 (m, 1H), 3.73 (s, 3H), 3.60 (t, J=7.0 Hz,
2H), 3.36 (s, 3H), 3.21 (s, 2H), 3.20–3.10 (m, 1H), 2.95–
2.37 (m, 10H), 2.19 (s, 3H), 1.90–1.75 (m, 2H), 1.70–
1.50 (br, 1H), 0.87 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
cyclohexyloxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-
8,13-dienoate 11-7j. 51% yield; 1H NMR (200 MHz,
CDCl3) d 7.33–7.09 (m, 4H), 5.85–5.69 (m, 1H), 5.57
(dd, J=15.8, 8.2Hz, 1H), 4.52 (s, 2H), 4.45–4.30 (m,
1H), 4.19–4.04 (m, 1H), 3.72(s, 3H), 3.44–3.62 (m,
1H), 3.20 (s, 2H), 3.19–3.10 (m, 1H), 2.96–2.36 (m,
8H), 2.18 (s, 3H), 2.06–1.14 (m, 13H), 0.86 (s, 9H),
0.03 (s, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methoxypropyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7d. 85% yield; H NMR (200 MHz, CDCl3)
d 7.40–6.92(m, 4H), 5.84–5.68 (m, 1H), 5.57 (dd,
J=15.3, 8.5 Hz, 1H), 4.44–4.28 (m, 1H), 4.15–4.05 (m,
1H), 3.72 (s, 3H), 3.45–3.25 (m, 5H), 3.25–3.10 (m, 3H),
2.96–2.35 (m, 10H), 2.18 (s, 3H), 2.00–1.73 (m, 4H),
0.86 (s, 9H), 0.04 (s, 3H), 0.02(s, 3H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-(1
-methoxyethyl)]phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7k. 64% yield; H NMR (200 MHz, CDCl3)
d 7.4–7.2 (m, 4H), 5.8–5.5 (m, 2H), 4.42 (s, 2H), 4.5–4.3
(m, 1H), 4.2–4.0 (m, 1H), 3.73 (s, 3H), 3.38 (m, 3H),
3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.4 (m, 8H), 2.21 (s,
3H), 1.9–1.7 (m, 3H), 0.89 (s, 9H), 0.05 (s, 6H).
1
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
ethoxymethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-7e. 84% yield; H NMR (200 MHz, CDCl3)
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
ethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-8a. 93% yield; H NMR (200 MHz, CDCl3) d 7.34–
1
1
d 7.46–7.02(m, 4H), 5.84–5.68 (m, 1H), 5.66–5.49 (m,
1H), 4.58–4.32(m, 3H), 4.18–4.04 (m, 1H), 3.72(s, 3H),
3.67–3.45 (m, 2H), 3.26–3.10 (m, 3H), 2.95–2.37 (m,
8H), 2.19 (s, 3H), 1.96–1.70 (m, 3H), 1.32–1.17 (m, 3H),
0.87 (s, 9H), 0.03 (s, 6H).
7.00 (m, 4H), 5.84–5.69 (m, 1H), 5.58 (dd, J=15.4,
8.5 Hz, 1H), 4.45–4.28 (m, 1H), 4.16–4.04 (m, 1H), 3.72
(s, 3H), 3.23–3.08 (m, 3H), 3.00–2.36 (m, 10H), 2.18 (s,
3H), 1.92–1.70 (m, 4H), 1.70–1.52 (br, 1H), 1.22 (t,
J=7.7 Hz, 3H), 0.86 (s, 3H), 0.03 (s, 6H).

998
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
vinyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-8b. 80% yield; H NMR (200 MHz, CDCl3) d 7.46–
7.04 (m, 4H), 6.69 (dd, J=17.8, 10.6 Hz, 1H), 5.86–5.66
(m, 2H), 5.56 (dd, J=15.4, 8.0 Hz, 1H), 5.23 (d,
J=10.6 Hz, 1H), 4.47–4.30 (m, 1H), 4.20–4.00 (m, 1H),
3.72 (s, 3H), 3.26–3.08 (m, 3H), 2.97–2.38 (m, 8H), 2.19
(s, 3H), 1.9–1.7 (m, 2H), 0.86 (s, 9H), 0.02 (m, 6H).
8.2Hz, 1H), 4.52–4.36 (m, 1H), 4.16–4.02(m, 1H), 3.71
(s, 3H), 3.24–3.08 (m, 3H), 2.96–2.32 (m, 8H), 2.18 (s,
3H), 1.90–1.50 (m, 3H), 0.88 (s, 9H), 0.02(s, 3H), 0.01
(s, 3H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-
(2-thienyl)]phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
11-8j. 90% yield; H NMR (200 MHz, CDCl3) d 7.55–
7.00 (m, 7H), 5.85–5.70 (m, 1H), 5.58 (dd, J=15.4,
8.4 Hz, 1H), 4.51–4.34 (m, 1H), 4.16–4.00 (m, 1H), 3.72
(s, 3H), 3.24–3.08 (m, 1H), 3.00–2.34 (m, 8H), 2.19 (s,
3H), 1.90–1.54 (m, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01
(s, 3H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
propyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-8c. 77% yield; H NMR (200 MHz, CDCl3) d 7.3–
7.25 (m, 1H), 7.07 (d, J=2Hz, 1H), 7.00 (d, J=5 Hz,
1H), 5.8–5.5 (m, 2H), 4.45–4.3 (m, 1H), 4.15–4.05 (m,
1H), 3.73 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.6
(m, 7H), 2.42 (dd, J=16, 4 Hz, 1H), 2.20 (s, 3H), 1.9–1.7
(m, 2H), 0.87 (s, 9H), 0.05 (s, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-
(2-furyl)]phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
11-8k. 86% yield; H NMR (200 MHz, CDCl3) d 7.55–
7.45 (m, 2H), 7.46 (d, J=1.5 Hz, 1H), 7.32(t, J=7.9 Hz,
1H), 7.13 (m, 1H), 6.65 (d, J=3.4 Hz, 1H), 6.46 (dd,
J=3.4, 1.5 Hz, 1H), 5.77 (dd, J=15, 5.7 Hz, 1H), 5.58
(dd, J=15, 8.5 Hz, 1H), 4.42(m, 1H), 4.08 (m, 1H), 3.72
(s, 3H), 3.20 (s, 2H), 3.13 (m, 1H), 2.98–2.34 (m, 8H),
2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
isopropyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dieno-
ate 11-8d. 63% yield; 1H NMR (200 MHz, CDCl3) d
7.12 (s, 4H), 5.8–5.5 (m, 2H), 4.4–4.3 (m, 1H), 4.2–4.0
(m, 1H), 3.72 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–
2.5 (m, 7H), 2.5–2.4 (m, 1H), 2.19 (s, 3H), 1.9–1.7 (m,
3H), 0.88 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
cyano)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
benzyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-8l. 60% yield; H NMR (200 MHz, CDCl3) d 7.3–
7.1 (m, 4H), 5.8–5.5 (m, 2H), 4.42 (s, 2H), 4.4–4.3 (m,
1H), 4.15–4.05 (m, 1H), 3.74 (s, 3H), 3.40 (m, 3H), 3.22
(s, 2H), 3.2–3.1 (m, 1H), 3.0–2.4 (m, 8H), 2.18 (s, 3H),
1.9–1.7 (m, 2H), 0.86 (s, 9H), 0.03 (s, 6H).
1
11-8e. 66% yield; H NMR (200 MHz, CDCl3) d 7.37–
7.00 (m, 9H), 5.75 (dd, J=16, 6.0 Hz, 1H), 5.57 (dd,
J=16, 8.5 Hz, 1H), 4.37 (m, 1H), 4.10 (m, 1H), 3.96 (s,
2H), 3.72 (s, 3H), 3.20 (s, 2H), 3.16 (m, 1H), 2.97–2.38
(m, 8H), 2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.87 (s, 9H), 0.03
(m, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
trifluoromethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-8m
.
72% yield; 1H NMR (200 MHz,
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-
(2-fluoroethyl)]phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-8f. 84% yield; H NMR (200 MHz, CDCl3)
d 7.30–7.04 (m, 4H), 5.81–5.50 (m, 2H), 4.80–4.30 (m,
3H), 4.18–4.05 (m, 1H), 3.68 (s, 3H), 3.21 (s, 2H), 3.21–
2.37 (m, 10H), 2.20 (s, 3H), 1.90–1.70 (m, 2H), 1.90–
1.60 (br, 1H), 0.88 (s, 9H), 0.04 (s, 6H).
CDCl3) d 7.63–7.28 (m, 4H), 5.82–5.66 (m, 1H), 5.57
(dd, J=15.5, 7.5 Hz, 1H), 4.49–4.32(m, 1H), 4.14–4.00
(m, 1H), 3.72 (s, 3H), 3.24–3.07 (m, 3H), 2.95–2.34 (m,
8H), 2.18 (s, 3H), 1.97–1.70 (m, 2H), 0.86 (s, 9H), 0.02
(s, 6H).
1
Methyl
9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-
(3,4-dichloro)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14a. 73% yield; 1H NMR (200 MHz,
CDCl3) d 7.40–7.30 (m, 2H), 7.13–7.04 (m, 1H), 5.80–
5.64 (m, 1H), 5.55 (dd, J=15.4, 7.6 Hz, 1H), 4.45–4.27
(m, 1H), 4.13–4.02 (m, 1H), 3.73 (s, 3H), 3.21 (s, 2H),
3.19–3.08 (m, 1H), 2.98–2.32 (m, 10H), 2.19 (s, 3H),
1.92–1.70 (m, 3H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-
(1-propynyl)]phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 11-8g. 69% yield; H NMR (200 MHz, CDCl3)
d 7.3–7.1 (m, 4H), 5.8–5.5 (m, 2H), 4.42 (s, 2H), 4.4–4.3
(m, 1H), 4.15–4.05 (m, 1H), 3.74 (s, 3H), 3.40 (m, 3H),
3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.4 (m, 8H), 2.18 (s,
3H), 1.9–1.7 (m, 2H), 0.86 (s, 9H), 0.03 (s, 6H).
1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-
(2-phenylethynyl)]phenyl-!-tetranor-3,7-dithiaprosta-
8,13-dienoate11-8h. 60% yield; 1H NMR (200 MHz,
CDCl3) d 7.60–7.16 (m, 9H), 5.83–5.48 (m, 2H), 4.48–
4.32(m, 1H), 4.20–4.00 (m, 1H), 3.72(s, 3H), 3.24–3.08
(m, 3H), 2.96–2.32 (m, 8H), 2.18 (s, 3H), 1.90–1.50 (m,
3H), 0.88 (s, 9H), 0.02(s, 3H), 0.01 (s, 3H).
Methyl
9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-
(3,4-dimethoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14b. 90% yield; 1H NMR (200 MHz,
CDCl3) d 6.98–6.60 (m, 3H), 5.82–5.53 (m, 2H), 4.40–
4.27 (m, 1H), 4.15–4.05 (m, 1H), 3.92–3.80 (m, 6H), 3.73
(s, 3H), 3.23–3.10 (m, 3H), 2.90–2.36 (m, 8H), 2.18 (s,
3H), 1.90–1.64 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
phenyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
11-8i. 75% yield; H NMR (200 MHz, CDCl3) d 7.66–
7.16 (m, 9H), 5.88–5.69 (m, 1H), 5.58 (dd, J=15.8,
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
chloro-4-methoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14c. Compound 16-14c was used for the next
reaction without further purification.
1

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
999
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methyl-4-methoxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14d. 89% yield; 1H NMR (200 MHz,
CDCl3) d 7.05–6.95 (m, 2H), 6.76 (d, J=8.6 Hz, 1H),
5.76 (dd, J=16, 6.1 Hz, 1H) 5.74 (dd, J=16, 5.5 Hz,
1H), 5.57 (dd, J=16, 8.3 Hz, 1H), 4.31 (m, 1H), 4.11 (m,
1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.21 (s, 2H), 3.16 (m,
1H), 2.97–2.36 (m, 8H), 2.19 (s, 6H), 1.9–1.7 (m, 2H),
0.87 (s, 9H), 0.04 (s, 6H).
CDCl3) d 7.12(s, 4H), 5.8–5.5 (m, 2H), 4.4–4.3 (m, 1H),
4.2–4.0 (m, 1H), 3.72 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m,
1H), 3.0–2.5 (m, 7H), 2.5–2.4 (m, 1H), 2.19 (s, 3H), 1.9–
1.7 (m, 3H), 0.88 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(2-
naphtyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate 16-15a
.
80% yield; 1H NMR (200 MHz, CDCl3) d 7.98–7.28
(m, 7H), 5.87–5.70 (m, 1H), 5.56 (dd, 1H, J=15,
8.8 Hz), 4.56–4.40 (m, 1H), 4.12–3.98 (m, 1H), 3.71 (s,
3H), 3.24–3.06 (m, 3H), 3.06–2.30 (m, 8H), 2.18 (s, 3H),
1.90–1.68 (m, 2H), 1.68–1.50 (br, 1H), 0.85 (s, 9H), 0.00
(s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methyl-4-hydroxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14e. 66% yield; 1H NMR (200 MHz,
CDCl3) d 6.99 (m, 1H), 6.90 (dd, J=8.2, 2.2 Hz, 1H),
6.69 (d, J=8.2Hz, 1H), 5.74 (dd, J=15, 5.8 Hz, 1H),
5.56 (m, 1H), 4.31 (m, 1H), 4.10 (m, 1H), 3.73 (s, 3H),
3.21 (s, 2H), 3.13 (m, 1H), 2.97–2.35 (m, 8H), 2.19 (s,
3H), 2.18 (s, 3H), 1.9–1.7 (m, 2H), 1.01 (s, 9H), 0.87 (s,
9H), 0.20 (s, 6H), 0.03 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(5-
isocoumaranyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
16-15b. 72% yield; H NMR (200 MHz, CDCl3) d 7.2–
7.0 (m, 3H), 5.76 (dd, J=15, 5.6 Hz, 1H), 5.57 (dd, 1H,
J=15, 8.1 Hz), 5.08 (s, 4H), 4.38 (m, 1H), 4.10 (m, 1H),
3.73 (s, 3H), 3.21 (s, 2H), 3.15 (m, 1H), 2.98–2.38 (m,
8H), 2.19 (s, 3H), 1.9–1.7 (m, 2H), 0.87 (s, 9H), 0.03 (s,
6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
chloro-6-methoxyphenyl)-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14f. Compound 16-14f was used for the next
reaction without further purification.
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
thienyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate 16-15c.
1
Methyl
9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-
71% yield; H NMR (200 MHz, CDCl3) d 7.3–7.25 (m,
(2,5-dimethylphenyl)-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14g. 86% yield; 1H NMR (200 MHz,
CDCl3) d 7.12–6.91 (m, 3H), 5.84–5.73 (m, 1H), 5.58
(dd, J=15.4, 8.7 Hz, 1H), 4.41–4.32(m, 1H), 4.18–4.04
(m, 1H), 3.72(s, 3H), 3.24–3.11 (m, 1H), 3.00–2.32(m,
8H), 2.29 (s, 6H), 2.18 (s, 3H), 1.90–1.72 (m, 2H), 0.86
(s, 9H), 0.04 (s, 3H), 0.02(s, 3H).
1H), 7.07 (d, J=2Hz, 1H), 7.00 (d, J=5 Hz, 1H), 5.8–
5.5 (m, 2H), 4.45–4.3 (m, 1H), 4.15–4.05 (m, 1H), 3.73
(s, 3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 3.0–2.6 (m, 7H),
2.42 (dd, J=16, 4 Hz, 1H), 2.20 (s, 3H), 1.9–1.7 (m, 2H),
0.87 (s, 9H), 0.05 (s, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(2-
thienyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate 16-15d
.
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(2-
methoxy-3-methylphenyl)-!-tetranor-3,7-dithiaprosta-
8,13-dienoate 16-14h. 65% yield; 1H NMR (200 MHz,
CDCl3) d 7.1–6.9 (m, 3H), 5.8–5.7 (m, 1H), 5.65–5.5 (m,
1H), 4.45–4.35 (m, 1H), 4.1–4.05 (m, 1H), 3.74 (s, 3H),
3.72 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m, 1H), 2.9–2.4 (m,
8H), 2.30 (s, 3H), 2.20 (s, 3H), 1.9–1.7 (m, 2H), 0.90 (s,
9H), 0.04 (s, 6H).
62% yield; 1H NMR (200 MHz, CDCl3) d 7.16 (dd,
J=5.1, 1.3 Hz, 1H), 7.93 (dd, J=5.1, 3.3 Hz, 1H), 6.91–
6.84 (m, 1H), 5.82–5.51 (m, 2H), 4.46–4.28 (m, 1H),
4.20–4.04 (m, 1H), 3.72 (s, 3H), 3.24–3.10 (m, 3H),
3.10–2.35 (m, 9H), 2.18 (s, 3H), 1.90–1.72 (m, 2H), 0.86
(s, 9H), 0.04–0.02(m, 6H).
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-[3-
(5-methoxymethyl)thienyl]-!-tetranor-3,7-dithiaprosta-
8,13-dienoate 16-15e. 56% yield; 1H NMR (200 MHz,
CDCl3) d 7.12(s, 4H), 5.8–5.5 (m, 2H), 4.4–4.3 (m, 1H),
4.2–4.0 (m, 1H), 3.72 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m,
1H), 3.0–2.5 (m, 7H), 2.5–2.4 (m, 1H), 2.19 (s, 3H), 1.9–
1.7 (m, 3H), 0.88 (s, 9H), 0.04 (s, 6H).
Methyl
(2,3-dimethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14i
68% yield; 1H NMR (200 MHz,
9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-
.
CDCl3) d 7.12(s, 4H), 5.8–5.5 (m, 2H), 4.4–4.3 (m, 1H),
4.2–4.0 (m, 1H), 3.72 (s, 3H), 3.22 (s, 2H), 3.2–3.1 (m,
1H), 3.0–2.5 (m, 7H), 2.5–2.4 (m, 1H), 2.19 (s, 3H), 1.9–
1.7 (m, 3H), 0.88 (s, 9H), 0.04 (s, 6H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(2-methyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6a. To a
stirred solution of 11-6a (124 mg, 0.20 mmol) and pyri-
dine (0.1 mL) in acetonitrile (3 mL) was added pyr-
Methyl
(3,5-dimethyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14j
91% yield; 1H NMR (200 MHz,
9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-
ꢀ
.
idinium poly(hydrogen fluoride) [(HF)n py, Aldrich,
CDCl3) d 6.89–6.82(m, 3H), 5.83–5.68 (m, 1H), 5.58
(dd, J=15.4, 8.2Hz, 1H), 4.43–4.28 (m, 1H), 4.18–4.04
(m, 1H), 3.72 (s, 3H), 3.24–3.08 (m, 1H), 2.96–2.32 (m,
8H), 2.29 (s, 6H), 2.18 (s, 3H), 1.90–1.72 (m, 2H), 0.86
(s, 9H), 0.06 (s, 3H), 0.02(s, 3H).
0.2mL]. The reaction mixture was stirred for 30 min
without cooling and then slowly poured into a hetero-
geneous mixture of EtOAc and saturated aqueous
NaHCO3 with stirring. The aqueous layer was extracted
with EtOAc and the combined organic layer was
washed with 1 N HCl, H2O and brine, and dried over
Na2SO4. The solvent was removed by evaporation and
the residual two diastereomers were separated by column
chromatography on silica gel (EtOAc/hexane, 1/1–3/1
Methyl 9-acetoxy-11,15-bis(t-butyldimethylsiloxy)-16-(3-
methoxy-5-methyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-
dienoate 16-14k. 61% yield; 1H NMR (200 MHz,

1000
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
then EtOAc/AcOH, 100/1) to give a more polar product
1
5.56 (dd, J=16, 8 Hz, 1H), 4.4–4.3 (m, 1H), 4.2–4.0 (m,
1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.22 (s, 2H), 3.3–3.2 (m,
1H), 2.94 (dd, J=16, 6 Hz, 1H), 2.8–2.4 (m, 7H), 2.22 (s,
3H), 1.9–1.7 (m, 2H).
12-6a as a yellow oil (32mg, 31%). H NMR (200 MHz,
CDCl3) d 7.20–7.07 (m, 4H), 5.76 (dd, J=15.4, 6.4 Hz,
1H), 5.56 (dd, J=15.4, 8.2Hz, 1H), 4.43–4.27 (m, 1H),
4.15–4.01 (m, 1H), 3.72(s, 3H), 3.72–3.16 (m, 3H),
3.08–2.40 (m, 8H), 2.33 (s, 3H), 2.19 (s, 3H), 1.92–1.71
(m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-ethoxy)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6i. 43%
yield; 1H NMR (200 MHz, CDCl3) d 7.28–7.15 (m, 1H),
6.80–6.70 (m, 3H), 5.75 (dd, J=15.4, 6.2Hz, 1H), 5.55
(dd, J=15.4, 8.0 Hz, 1H), 4.41–4.31 (m, 1H), 4.10–4.05
(m, 1H), 4.02(q, J=7.0 Hz, 2H), 3.73 (s, 3H), 3.22 (s,
2H), 3.22–3.18 (m, 1H), 3.00–2.00 (br, 2H), 2.97–2.42
(m, 8H), 2.20 (s, 3H), 1.88–1.72 (m, 2H), 1.40 (t,
J=7.0 Hz, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6b. 41%
1
yield; H NMR (200 MHz, CDCl3) d 7.19 (m, 1H), 7.03
(m, 3H), 5.76 (dd, J=15, 6 Hz), 5.58 (dd, J=15, 8 Hz),
4.37 (m, 1H), 4.08 (m, 1H), 3.73 (s, 3H), 3.22 (s, 2H),
3.21 (m, 1H), 3.0–2.4 (m, 8H), 2.33 (s, 3H), 2.20 (s, 3H),
1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(4-ethoxy)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6j. 40%
yield; 1H NMR (200 MHz, CDCl3) d 7.12(d, J=8.4 Hz,
2H), 6.83 (d, J=8.4 Hz, 2H), 5.74 (dd, J=15.4, 6.2Hz,
1H), 5.55 (dd, J=15.4, 8.4 Hz, 1H), 4.36–4.27 (m, 1H),
4.10–4.04 (m, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.73 (s, 3H),
3.22 (s, 2H), 3.22–3.15 (m, 1H), 2.91 (ddd, J=16.6, 6.8,
1.2 Hz, 1H), 2.80–2.40 (m, 7H), 2.50–2.20 (br, 2H), 2.20
(s, 3H), 1.87–1.73 (m, 2H), 1.40 (t, J=7.0 Hz, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(4-methyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6c. 41%
yield; H NMR (200 MHz, CDCl3) d 7.09 (s, 4H), 5.74
(dd, J=15, 6 Hz, 1H), 5.56 (dd, J=15, 8 Hz, 1H), 4.35–
4.3 (m, 1H), 4.1–4.05 (m, 1H), 3.70 (s, 3H), 3.22 (s, 2H),
3.25–3.2 (m, 1H), 2.92 (dd, J=17, 7 Hz, 1H), 2.83 (dd,
J=14, 5 Hz, 1H), 2.8–2.6 (m, 4H), 2.57 (dt, J=14, 8 Hz,
1H), 2.45 (dd, J=17, 3 Hz, 1H), 2.30 (s, 3H), 2.16 (s,
3H), 1.9–1.8 (m, 2H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methylthio)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6k. 42%
yield; 1H NMR (200 MHz, CDCl3) d 7.22 (m, 1H),
7.15–7.05 (m, 2H), 6.99 (m, 1H), 5.73 (dd, J=15, 6 Hz,
1H), 5.55 (dd, J=15, 8 Hz, 1H), 4.36 (m, 1H), 4.07 (m,
1H), 3.73 (s, 3H), 3.22 (s, 2H), 3.21 (m, 1H), 2.95–2.4
(m, 8H), 2.47 (s, 3H), 2.20 (s, 3H), 1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-chloro)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6d. 46%
yield; H NMR (200 MHz, CDCl3) d 7.25–7.1 (m, 4H),
5.73 (dd, J=16, 6 Hz, 1H), 5.55 (dd, J=16, 8 Hz), 4.37
(m, 1H), 4.07 (m, 1H), 3.74 (s, 3H), 3.23 (s, 2H), 3.21
(m, 1H), 3.0–2.4 (m, 8H), 2.20 (s, 3H), 1.9–1.7 (m, 2H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(4-chloro)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6e. 47%
yield; H NMR (200 MHz, CDCl3) d 7.27 (d, J=8 Hz,
Methyl 9-acetoxy-11,15-dihydroxy-16-(4-methylthio)phe-
nyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6l. 43%
yield; H NMR (200 MHz, CDCl3) d 7.25–7.1 (m, 4H),
1
1
2H), 7.16 (d, J=8 Hz, 2H), 5.74 (dd, J=16, 6 Hz, 1H),
5.55 (dd, J=16, 8 Hz, 1H), 4.4–4.3 (m, 1H), 4.1–4.0 (m,
1H), 3.73 (s, 3H), 3.22 (s, 2H), 3.3–3.2 (m, 1H), 2.94 (dd,
J=16, 6 Hz, 1H), 2.9–2.4 (m, 7H), 2.20 (s, 3H), 1.9–1.8
(m, 2H).
5.73 (1H, J=16, 6 Hz, 1H), 5.55 (dd, J=16, 8 Hz, 1H),
4.34 (m, 1H), 4.08 (m, 1H), 3.73 (s, 3H), 3.22 (s, 2H),
3.20 (m, 1H), 3.0–2.4 (m, 8H), 2.47 (s, 3H), 2.20 (s, 3H),
1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-hydroxy)phenyl-
Methyl 9-acetoxy-11,15-dihydroxy-16-(2-methoxy)phe-
nyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6f. 45%
yield; 1H NMR (200 MHz, CDCl3) d 7.28–7.08 (m, 2H),
6.96–6.80 (m, 2H), 5.71 (dd, J=15.4, 6.4 Hz, 1H), 5.52
(dd, J=15.4, 8.2Hz, 1H), 4.47–4.32 (m, 1H), 4.11–3.99
(m, 1H), 3.82(s, 3H), 3.71 (s, 3H), 3.24–3.10 (m, 3H),
2.98–2.36 (m, 8H), 2.18 (s, 3H), 1.88–1.68 (m, 2H).
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6m. 35%
yield; 1H NMR (200 MHz, CDCl3) d 7.22–7.06 (m, 1H),
6.94–6.56 (m, 4H), 5.72(dd, J=15.4, 6.6 Hz, 1H), 5.52
(dd, J=15.4, 8.0 Hz, 1H), 4.45–4.25 (m, 1H), 4.14–3.98
(m, 1H), 3.73 (s, 3H), 3.30–3.12(m, 3H), 3.02–2.36 (m,
10H), 2.20 (s, 3H), 1.92–1.70 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(4-hydroxy)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6n. 38%
yield; 1H NMR (200 MHz, CDCl3) d 7.04 (d, J=8.4 Hz,
2H), 6.75 (d, J=8.4 Hz, 2H), 6.60–6.40 (br, 1H), 5.69
(dd, J=15.4, 6.2Hz, 1H), 5.50 (dd, J=15.4, 8.0 Hz,
1H), 4.35–4.25 (m, 1H), 4.13–4.00 (m, 1H), 3.74 (s, 3H),
3.60–3.20 (br, 1H), 3.22 (s, 2H), 3.22–3.12 (m, 1H),
2.94–2.42 (m, 8H), 2.20 (s, 3H), 2.20–2.00 (br, 1H),
1.82–1.70 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methoxy)phe-
nyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6g. 39%
yield in two steps; H NMR (200 MHz, CDCl3) d 7.25–
7.15 (m, 1H), 6.8–6.7 (m, 3H), 5.77 (dd, J=15, 6 Hz,
1H), 5.57 (dd, J=15, 8 Hz, 1H), 4.4–4.3 (m, 1H), 4.15–
4.0 (m, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.22 (s, 2H), 3.3–
3.2 (m, 1H), 3.0–2.4 (m, 9H), 2.20 (s, 3H), 1.9–1.7 (m,
3H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(4-methoxy)phe-
nyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6h. 45%
yield; H NMR (200 MHz, CDCl3) d 7.13 (d, J=8 Hz,
2H), 6.85 (d, J=8 Hz, 2H), 5.76 (dd, J=16, 6 Hz, 1H),
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methylsulfonyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6o.
39% yield; 1H NMR (200 MHz, CDCl3) d 7.82–7.78
(m, 2H), 7.54–7.45 (m, 2H), 5.75 (dd, J=15.4, 5.8 Hz,
1

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
1001
1H), 5.54 (dd, J=15.4, 8.0 Hz, 1H), 4.48–4.39 (m, 1H),
4.10–4.02 (m, 1H), 3.73 (s, 3H), 3.23 (s, 2H), 3.23–3.17
(m, 1H), 3.06 (s, 3H), 2.96–2.20 (m, 10H), 2.19 (s, 3H),
1.87–1.73 (m, 2H).
3.31–3.14 (m, 3H), 3.02–3.23 (m, 12H), 2.19 (s, 3H),
1.97–1.72(m, 4H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-ethoxymethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7e.
45% yield; 1H NMR (200 MHz, CDCl3) d 7.34–7.09
(m, 4H), 5.75 (dd, J=15.4, 6.0 Hz, 1H), 5.53 (dd,
J=15.4, 8.4 Hz, 1H), 4.47 (s, 2H), 4.45–4.32 (m, 1H),
4.10–3.98 (m, 1H), 3.73 (s, 3H), 3.57 (q, J=7.0 Hz, 2H),
3.27–3.14 (m, 3H), 2.95–2.24 (m, 10H), 2.19 (s, 3H),
1.96–1.70 (m, 3H), 1.25 (t, J=7.0 Hz, 3H).
Methyl
9-acetoxy-11,15-dihydroxy-16-(4-methylsulfo-
nyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6p.
40% yield; 1H NMR (200 MHz, CDCl3) d 7.85 (d,
J=8 Hz, 2H), 7.44 (d, J=8 Hz, 2H), 5.72 (dd, J=16,
6 Hz, 1H), 5.54 (dd, J=16, 8 Hz, 1H), 4.40 (m, 1H), 4.05
(m, 1H), 3.73 (s, 3H), 3.23 (s, 2H), 3.21 (m, 1H), 3.04 (s,
3H), 2.99–2.52 (m, 7H), 2.45 (dd, J=17, 3 Hz, 1H), 2.20
(s, 3H), 1.82(m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-propoxymethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7f.
36% yield; 1H NMR (200 MHz, CDCl3) d 7.33–7.10
(m, 4H), 5.96 (ddt, J=17.2, 10.2, 6.0 Hz, 1H), 5.74 (dd,
J=15.4, 5.8 Hz, 1H), 5.53 (dd, J=15.4, 8.2Hz, 1H),
5.38–5.17 (m, 2H), 4.49 (s, 2H), 4.42–4.31 (m, 1H),
4.12–4.00 (m, 3H), 3.73 (s, 3H), 3.25–3.14 (m, 1H),
2.96–2.40 (m, 10H), 2.19 (s, 3H), 1.90–1.72 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methoxymethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
12-6q.
48% yield; 1H NMR (200 MHz, CDCl3) d 7.30 (t,
J=8 Hz, 1H), 7.2–7.1 (m, 3H), 5.77 (dd, J=15, 7 Hz,
1H), 5.54 (dd, J=15, 9 Hz, 1H), 4.42(d, J=6 Hz, 2H),
4.45–4.4 (m, 1H), 4.1–4.0 (m, 1H), 3.74 (s, 3H), 3.42(m,
3H), 3.22 (s, 2H), 3.25–3.2 (m, 1H), 3.0–2.6 (m, 8H),
2.48 (dd, J=18, 5 Hz, 1H), 2.19 (s, 3H), 1.9–1.8 (m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-allyloxymethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7g.
41% yield; 1H NMR (200 MHz, CDCl3) d 7.43–7.10
(m, 4H), 6.08–5.85 (m, 1H), 5.84–5.68 (m, 1H), 5.57 (dd,
J=15.4, 8.4 Hz, 1H), 5.39–5.15 (m, 2H), 4.50 (s, 2H),
4.46–4.30 (m, 1H), 4.19–3.97 (m, 3H), 3.72(s, 3H),
3.20 (s, 2H), 3.19–3.09 (m, 1H), 2.95–2.37 (m, 8H),
2.19 (s, 3H), 1.92–1.68 (m, 2H), 0.86 (s, 9H), 0.03 (m,
6H).
Methyl
9-acetoxy-11,15-dihydroxy-16-(4-methoxyme-
thyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-6r.
49% yield; 1H NMR (200 MHz, CDCl3) d 7.28 (d,
J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 5.77 (dd, J=15,
6 Hz, 1H), 5.56 (dd, J=15, 8 Hz, 1H), 4.42(s, 2H), 4.45–
4.3 (m, 1H), 4.15–4.0 (m, 1H), 3.73 (s, 3H), 3.38 (m,
3H), 3.3–3.2 (m, 1H), 3.23 (s, 2H), 3.0–2.3 (m, 9H), 2.20
(s, 3H), 1.9–1.8 (m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-isopropoxyme-
thyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
12-7h. 43% yield; H NMR (200 MHz, CDCl3) d 7.30
(t, J=8 Hz, 1H), 7.2–7.1 (m, 3H), 5.77 (dd, J=15, 7 Hz,
1H), 5.54 (dd, J=15, 9 Hz, 1H), 4.42(d, J=6 Hz, 2H),
4.45–4.4 (m, 1H), 4.1–4.0 (m, 1H), 3.74 (s, 3H), 3.42
(m, 3H), 3.22 (s, 2H), 3.25–3.2 (m, 1H), 3.0–2.6 (m,
8H), 2.48 (dd, J=18, 5 Hz, 1H), 2.19 (s, 3H), 1.9–1.8
(m, 3H).
Methyl
9-acetoxy-11,15-dihydroxy-16-(3-hydroxyme-
1
thyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7a.
41% yield; 1H NMR (200 MHz, CDCl3) d 7.31–7.07
(m, 4H), 5.68 (dd, J=15, 6.4 Hz, 1H), 5.49 (dd, J=15,
8.6 Hz, 1H), 4.61 (s, 2H), 4.34 (m, 1H), 4.00 (m, 1H),
3.72 (s, 3H), 3.21 (s, 2H), 3.17 (m, 1H), 2.90–2.38 (m,
10H), 2.19 (s, 3H), 1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methylthiomethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7b. 43%
yield; 1H NMR (200 MHz, CDCl3) d 7.30–7.05 (m, 4H),
5.73 (dd, J=15.6, 6.2Hz, 1H), 5.55 (dd, J=15.4, 8.0 Hz,
1H), 4.44–4.30 (m, 1H), 4.14–4.02(m, 1H), 3.73 (s, 3H),
3.65 (s, 2H), 3.26–3.14 (m, 3H), 2.95–2.26 (m, 10H),
2.19 (s, 3H), 2.00 (s, 3H), 1.90–1.75 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-phenoxymethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7i.
40% yield; 1H NMR (200 MHz, CDCl3) d 7.36–7.12
(m, 6H), 6.96 (m, 3H), 5.72(dd, J=15, 6.3 Hz, 1H), 5.54
(dd, J=15, 8.3 Hz, 1H), 5.02(s, 2H), 4.36 (m, 1H), 4.05
(m, 1H), 3.72 (s, 3H), 3.20 (s, 2H), 3.19 (m, 1H), 2.95–
2.39 (m, 10H), 2.18 (s, 3H), 1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methoxyethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7c.
42% yield; 1H NMR (200 MHz, CDCl3) d 7.27–7.02
(m, 4H), 5.74 (dd, J=15.6, 6.2Hz, 1H), 5.56 (dd,
J=15.6, 8.2Hz, 1H), 4.40–4.31 (m, 1H), 4.10–4.03 (m,
1H), 3.73 (s, 3H), 3.60 (t, J=7.0 Hz, 2H), 3.35 (s, 3H),
3.22 (s, 2H), 3.22–3.16 (m, 1H), 3.00–2.40 (m, 9H), 2.20
(s, 3H), 2.10–2.00 (br, 1H), 1.89–1.73 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-cyclohexyloxy-
methyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
12-7j. 46% yield; H NMR (200 MHz, CDCl3) d 7.32–
7.08 (m, 4H), 5.74 (dd, J=15.4, 6.2Hz, 1H), 5.57 (dd,
J=15.4, 8.4 Hz, 1H), 4.51 (s, 2H), 4.45–4.32 (m, 1H),
4.09–3.96 (m, 1H), 3.73 (s, 3H), 3.45–3.28 (m, 1H),
3.26–3.02 (m, 3H), 2.96–2.40 (m, 10H), 2.19 (s, 3H),
2.06–1.15 (m, 12H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methoxypropyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
12-7d.
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(1-methoxyethyl)]-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-7k.
37% yield; 1H NMR (200 MHz, CDCl3) d 7.28 (d,
J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 5.77 (dd, J=15,
6 Hz, 1H), 5.56 (dd, J=15, 8 Hz, 1H), 4.42(s, 2H), 4.45–
46% yield; 1H NMR (200 MHz, CDCl3) d 7.30–6.97
(m, 4H), 5.74 (dd, J=15.4, 6.4 Hz, 1H), 5.55 (dd,
J=15.4, 8.0 Hz, 1H), 4.44–4.28 (m, 1H), 4.14–4.01 (m,
1H), 3.72(s, 3H), 3.38 (t, J=6.4 Hz, 2H), 3.34 (s, 3H),

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T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
4.3 (m, 1H), 4.15–4.0 (m, 1H), 3.73 (s, 3H), 3.38 (m,
3H), 3.3–3.2 (m, 1H), 3.23 (s, 2H), 3.0–2.3 (m, 9H), 2.20
(s, 3H), 1.9–1.8 (m, 3H).
8H), 2.48 (dd, J=18, 5 Hz, 1H), 2.19 (s, 3H), 1.9–1.8 (m,
3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(2-phenylethy-
nyl)]phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
12-8h. 31% yield; H NMR (200 MHz, CDCl3) d 7.59–
7.15 (m, 9H), 5.74 (dd, J=15.6, 6.6 Hz, 1H), 5.54 (dd,
J=15.6, 8.2Hz, 1H), 4.45–4.31 (m, 1H), 4.12–4.00 (m,
1H), 3.72 (s, 3H), 3.26–3.12 (m, 3H), 2.94–2.38 (m,
10H), 2.18 (s, 3H), 1.89–1.70 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-ethyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8a. 43%
yield; 1H NMR (200 MHz, CDCl3) d 7.25–6.97 (m, 4H),
5.76 (dd, J=15.4, 5.8 Hz, 1H), 5.58 (dd, J=15.4, 8.0 Hz,
1H), 4.44–4.30 (m, 1H), 4.14–4.04 (m, 1H), 3.73 (s, 3H),
3.18–3.16 (m, 3H), 3.00–2.40 (m, 10H), 2.20 (s, 3H),
2.12–1.7 (m, 4H), 1.22 (t, J=7.7 Hz, 3H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-phenyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8i. 44%
yield; 1H NMR (200 MHz, CDCl3) d 7.64–7.15 (m, 9H),
5.75 (dd, J=15.4, 6.6 Hz, 1H), 5.55 (dd, J=15.4, 8.0 Hz,
1H), 4.48–4.32(m, 1H), 4.12–4.00 (m, 1H), 3.72(s, 3H),
3.26–3.12 (m, 3H), 2.98–2.38 (m, 10H), 2.17 (s, 3H),
1.88–1.66 (m, 2H).
Methyl
9-acetoxy-11,15-dihydroxy-16-(3-vinyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8b. 40%
yield; 1H NMR (200 MHz, CDCl3) d 7.46–7.04 (m, 4H),
6.69 (dd, J=17.8, 10.6 Hz, 1H), 5.86–5.66 (m, 2H), 5.56
(dd, J=15.4, 8.0 Hz, 1H), 5.23 (d, J=10.6 Hz, 1H),
4.47–4.30 (m, 1H), 4.20–4.00 (m, 1H), 3.72 (s, 3H),
3.26–3.08 (m, 3H), 2.97–2.38 (m, 8H), 2.19 (s, 3H), 1.9–
1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(2-thienyl)]phe-
nyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8j. 44%
yield; 1H NMR (200 MHz, CDCl3) d 7.50–7.42(m, 2H),
7.34–7.23 (m, 3H), 7.17–7.09 (m, 1H), 7.06 (dd, J=5.1,
3.3 Hz, 1H), 5.74 (dd, J=15.3, 6.6 Hz, 1H), 5.55 (dd,
J=15.3, 8.2Hz, 1H), 4.45–4.31 (m, 1H), 4.12–4.00 (m,
1H), 3.72 (s, 3H), 3.26–3.12 (m, 3H), 2.94–2.38 (m,
10H), 2.18 (s, 3H), 1.86–1.66 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-propyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8c. 44%
1
yield; H NMR (200 MHz, CDCl3) d 7.3–7.2(m, 1H),
7.06 (d, J=2Hz, 1H), 6.99 (dd, J=5, 2Hz, 1H), 5.76
(dd, J=15, 6 Hz, 1H), 5.58 (dd, J=15, 8 Hz, 1H), 4.45–
4.3 (m, 1H), 4.15–4.05 (m, 1H), 3.73 (s, 3H), 3.3–3.2(m,
1H), 3.22 (s, 2H), 3.0–2.4 (m, 9H), 2.20 (s, 3H), 1.9–1.7
(m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(2-furyl)]phenyl
-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8k. 40%
yield; 1H NMR (200 MHz, CDCl3) d 7.55–7.45 (m, 2H),
7.46 (d, J=1.8 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.10 (m,
1H), 6.64 (d, J=3.3 Hz), 6.46 (dd, J=3.3, 1.8 Hz, 1H),
5.72(dd, J=15, 6.3 Hz, 1H), 5.55 (dd, J=15, 8.0 Hz,
1H), 4.38 (m, 1H), 4.07 (m, 1H), 3.72(s, 3H), 3.20 (s,
2H), 3.19 (m, 1H), 2.94–2.38 (m, 10H), 2.18 (s, 3H), 1.9–
1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-isopropyl)phe-
nyl - ! - tetranor - 3,7 - dithiaprosta - 8,13 - dienoate 12-8d.
47% yield; 1H NMR (200 MHz, CDCl3) d 7.13 (d,
J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 5.76 (dd, J=16,
6 Hz, 1H), 5.56 (dd, J=16, 8 Hz, 1H), 4.4–4.3 (m, 1H),
4.2–4.0 (m, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.22 (s, 2H),
3.3–3.2(m, 1H), 2.94 (dd, J=16, 6 Hz, 1H), 2.8–2.4 (m,
7H), 2.22 (s, 3H), 1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-cyano)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8l. 31%
yield; H NMR (200 MHz, CDCl3) d 7.30 (t, J=8 Hz,
1H), 7.2–7.1 (m, 3H), 5.77 (dd, J=15, 7 Hz, 1H), 5.54
(dd, J=15, 9 Hz, 1H), 4.42(d, J=6 Hz, 2H), 4.45–4.4
(m, 1H), 4.1–4.0 (m, 1H), 3.74 (s, 3H), 3.42(m, 3H),
3.22 (s, 2H), 3.25–3.2 (m, 1H), 3.0–2.6 (m, 8H), 2.48 (dd,
J=18, 5 Hz, 1H), 2.19 (s, 3H), 1.9–1.8 (m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-benzyl)phenyl-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8e. 43%
yield; 1H NMR (200 MHz, CDCl3) d 7.34–7.12(m, 6H),
7.1–6.95 (m, 3H), 5.71 (dd, J=16, 6.2Hz, 1H), 5.55 (dd,
J=16, 8.3 Hz, 1H), 4.32(m, 1H), 4.04 (m, 1H), 3.95 (s,
2H), 3.72 (s, 3H), 3.21 (s, 2H), 3.19 (m, 1H), 2.95–2.38
(m, 10H), 2.19 (s, 3H), 1.9–1.7 (m, 2H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(2-fluoroethyl)]-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8f.
40% yield; 1H NMR (200 MHz, CDCl3) d 7.29–7.07
(m, 4H), 5.74 (dd, J=15.4, 6.2Hz, 1H), 5.56 (dd,
J=15.4, 8.4 Hz, 1H), 4.63 (q, J=6.8 Hz, 2H,), 4.41–4.31
(m, 1H), 4.09–4.00 (m, 1H), 3.73 (s, 3H), 3.22 (s, 2H),
3.22–3.17 (m, 1H), 3.08–2.41 (m, 10H), 2.40–1.70 (br,
2H), 2.20 (s, 3H), 1.88–1.72 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-trifluoromethyl)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8m
.
44% yield; 1H NMR (200 MHz, CDCl3) d 7.54–7.33
(m, 4H), 5.73 (dd, J=15.4, 6.2Hz, 1H), 5.55 (dd,
J=15.5, 7.8 Hz, 1H), 4.46–4.32(m, 1H), 4.12–3.99 (m,
1H), 3.72 (s, 3H), 3.28–3.14 (m, 3H), 2.98–2.38 (m,
10H), 2.19 (s, 3H), 1.90–1.72 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3,4-dichloro)phe-
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(1-propynyl)]-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 12-8g.
39% yield; 1H NMR (200 MHz, CDCl3) d 7.30 (t,
J=8 Hz, 1H), 7.2–7.1 (m, 3H), 5.77 (dd, J=15, 7 Hz,
1H), 5.54 (dd, J=15, 9 Hz, 1H), 4.42(d, J=6 Hz, 2H),
4.45–4.4 (m, 1H), 4.1–4.0 (m, 1H), 3.74 (s, 3H), 3.42
(m, 3H), 3.22 (s, 2H), 3.25–3.2 (m, 1H), 3.0–2.6 (m,
nyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 17-14a.
37% yield; 1H NMR (200 MHz, CDCl3) d 7.46–7.26
(m, 2H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 5.70 (dd,
J=15.4, 6.4 Hz, 1H), 5.53 (dd, J=15.4, 7.8 Hz, 1H),
4.46–4.24 (m, 1H), 4.18–3.98 (m, 1H), 3.73 (s, 3H),
3.32–3.14 (m, 3H), 3.00–2.34 (m, 10H), 2.19 (s, 3H),
1.92–1.70 (m, 3H).

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
1003
Methyl 9-acetoxy-11,15-dihydroxy-16-(3,4-dimethoxy)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 17-14b
Methyl 9-acetoxy-11,15-dihydroxy-16-(2,3-dimethyl)phe-
nyl - ! - tetranor- 3,7 - dithiaprosta - 8,13 - dienoate 17-14i
.
.
42% yield; 1H NMR (200 MHz, CDCl3) d 6.85–6.71
(m, 3H), 5.75 (dd, J=15.6, 6.2Hz, 1H) 5.57 (dd,
J=15.6, 8.0 Hz, 1H), 4.41–4.27 (m, 1H), 4.15–4.05 (m,
1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H), 3.28–3.16
(m, 3H), 3.00–2.36 (m, 10H), 2.19 (s, 3H), 1.90–1.70 (m,
2H).
46% yield; H NMR (200 MHz, CDCl3) d 7.09 (s, 4H),
5.74 (dd, J=15, 6 Hz, 1H), 5.56 (dd, J=15, 8 Hz, 1H),
4.35–4.3 (m, 1H), 4.1–4.05 (m, 1H), 3.70 (s, 3H), 3.22 (s,
2H), 3.25–3.2 (m, 1H), 2.92 (dd, J=17, 7 Hz, 1H), 2.83
(dd, J=14, 5 Hz, 1H), 2.8–2.6 (m, 4H), 2.57 (dt, J=14,
8 Hz, 1H), 2.45 (dd, J=17, 3 Hz, 1H), 2.30 (s, 3H), 2.16
(s, 3H), 1.9–1.8 (m, 2H).
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-chloro-4-meth-
oxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
17-14c. 39% yield in two steps; 1H NMR (200 MHz,
CDCl3) d 7.23 (s, 1H), 7.08 (dd, J=8, 2Hz, 1H), 6.86
(d, J=8 Hz, 1H), 5.75 (dd, J=16, 6 Hz, 1H), 5.56 (dd,
J=16, 8 Hz, 1H), 4.4–4.25 (m, 1H), 4.15–4.05 (m, 1H),
3.89 (s, 3H), 3.74 (s, 3H), 3.3–3.2 (m, 1H), 3.23 (s, 2H),
2.95 (ddd, J=17, 6, 2 Hz, 1H), 2.8–2.5 (m, 7H), 2.46
(dd, J=17, 3 Hz, 1H), 2.38 (d, J=7 Hz, 1H), 2.21 (s,
3H), 1.9–1.7 (m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3,5-dimethyl)phe-
nyl - ! - tetranor- 3,7 - dithiaprosta - 8,13 - dienoate 17-14j
.
46% yield; 1H NMR (200 MHz, CDCl3) d 6.92–6.72
(m, 3H), 5.73 (dd, J=15.4, 6.2Hz, 1H), 5.58 (dd,
J=15.4, 7.6 Hz, 1H), 4.40–4.24 (m, 1H), 4.15–4.03 (m,
1H), 3.73 (s, 3H), 3.27–3.14 (m, 1H), 2.97–2.38 (m,
10H), 2.28 (s, 6H), 2.19 (s, 3H), 1.90–1.72 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methoxy-5-me-
thyl)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methyl-4-meth-
oxy)phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate
17-14k. 44% yield; H NMR (200 MHz, CDCl3) d 7.25–
7.15 (m, 1H), 6.8–6.7 (m, 3H), 5.77 (dd, J=15, 6 Hz,
1H), 5.57 (dd, J=15, 8 Hz, 1H), 4.4–4.3 (m, 1H), 4.15–4.0
(m, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.22 (s, 2H), 3.3–3.2
(m, 1H), 3.0–2.4 (m, 9H), 2.20 (s, 3H), 1.9–1.7 (m, 3H).
1
17-14d. 44% yield; H NMR (200 MHz, CDCl3) d 7.05–
6.95 (m, 2H), 6.75 (d, J=9.0 Hz, 1H), 5.75 (dd, J=16,
6.0 Hz, 1H), 5.57 (dd, J=16, 8.0 Hz, 1H), 4.31 (m, 1H),
4.10 (m, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.22 (s, 2H), 3.21
(m, 1H), 2.99–2.41 (m, 10H), 2.20 (s, 6H), 1.9–1.7 (m,
2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(2-naphtyl)-!-tet-
ranor-3,7-dithiaprosta-8,13-dienoate 17-15a. 45% yield;
1H NMR (200 MHz, CDCl3) d 7.84–7.30 (m, 7H), 5.77
(dd, 1H, J=15.4, 6.2Hz), 5.54 (dd, 1H, J=15.4,
8.0 Hz), 4.54–4.38 (m, 1H), 4.10–3.98 (m, 1H), 3.71 (s,
3H), 3.24–3.14 (m, 3H), 3.00 (d, J=6.6 Hz, 2H), 2.93–
2.30 (m, 8H), 2.18 (s, 3H), 1.81–1.63 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-methyl-4-hydroxy)-
phenyl-!-tetranor-3,7-dithiaprosta-8,13-dienoate 17-14e
.
44% yield; 1H NMR (200 MHz, CDCl3) d 6.95–6.85
(m, 2H), 6.67 (d, J=8.0 Hz, 1H), 6.23 (s, 1H), 5.69 (dd,
J=15, 6.4 Hz, 1H), 5.52(dd, J=15, 8.3 Hz, 1H), 4.28
(m, 1H), 4.06 (m, 1H), 3.73 (s, 3H), 3.22 (s, 2H), 3.19
(m, 1H), 2.96–2.41 (m, 10H), 2.20 (s, 6H), 1.9–1.7 (m,
2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(5-isocoumaranyl)-
!-tetranor-3,7-dithiaprosta-8,13-dienoate 17-15b. 41%
1
yield; H NMR (200 MHz, CDCl3) d 7.2–7.0 (m, 3H),
5.74 (dd, J=15, 6.4 Hz, 1H), 5.55 (dd, J=15, 8.2Hz,
1H), 5.07 (s, 4H), 4.35 (m, 1H), 4.08 (m, 1H), 3.73 (s,
3H), 3.22 (s, 2H), 3.21 (m, 1H), 2.97–2.39 (m, 10H), 2.20
(s, 3H), 1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-chloro-6-methoxy-
phenyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate
17-14f.
1
26% yield in two steps; H NMR (200 MHz, CDCl3) d
7.15 (dd, J=8.4, 2.8 Hz, 1H), 7.12 (d, J=2.8 Hz, 1H),
6.78 (d, J=8.4 Hz, 1H), 5.72(dd, J=16, 6.3 Hz, 1H),
5.54 (dd, J=16, 7.8 Hz, 1H), 4.41 (m, 1H), 4.08 (m, 1H),
3.82 (s, 3H), 3.74 (s, 3H), 3.23 (s, 2H), 3.20 (m, 1H),
2.98–2.41 (m, 10H), 2.20 (s, 3H), 1.9–1.7 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(3-thienyl)-!-tet-
ranor-3,7-dithiaprosta-8,13-dienoate 17-15c. 39% yield;
1H NMR (200 MHz, CDCl3) d 7.3–7.2(m, 1H), 7.06 (d,
J=2Hz, 1H), 6.99 (dd, J=5, 2Hz, 1H), 5.76 (dd, J=15,
6 Hz, 1H), 5.58 (dd, J=15, 8 Hz, 1H), 4.45–4.3 (m, 1H),
4.15–4.05 (m, 1H), 3.73 (s, 3H), 3.3–3.2(m, 1H), 3.22(s,
2H), 3.0–2.4 (m, 9H), 2.20 (s, 3H), 1.9–1.7 (m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(2,5-dimethylphe-
nyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate 17-14g
.
48% yield; 1H NMR (200 MHz, CDCl3) d 7.07–6.86
(m, 3H), 5.57 (dd, J=15.4, 6.6 Hz, 1H), 5.58 (dd,
J=15.4, 8.4 Hz, 1H), 4.39–4.25 (m, 1H), 4.14–4.04 (m,
1H), 3.72(s, 3H), 3.42–3.11 (m, 1H), 3.00–.232(m,
10H), 2.27 (s, 6H), 2.19 (s, 3H), 1.90–1.72 (m, 2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(2-thienyl)-!-tet-
ranor-3,7-dithiaprosta-8,13-dienoate 17-15d. 46% yield;
1H NMR (200 MHz, CDCl3) d 7.16 (dd, J=5.2, 1.2 Hz,
1H), 6.94 (dd, J=5.2, 3.4 Hz, 1H), 6.89–6.84 (m, 1H),
5.75 (dd, J=15.4, 5.6 Hz, 1H), 5.61 (dd, J=15.4, 7.8 Hz,
1H), 4.44–4.30 (m, 1H), 4.16–4.03 (m, 1H), 3.73 (s, 3H),
3.28–3.17 (m, 3H), 3.17–2.24 (m, 10H), 2.19 (s, 3H),
1.92–1.72 (m, 3H).
Methyl 9-acetoxy-11,15-dihydroxy-16-(2-methoxy-3-me-
thylphenyl)-!-tetranor-3,7-dithiaprosta-8,13-dienoate
1
17-14h. 50% yield; H NMR (200 MHz, CDCl3) d 7.1–
6.95 (m, 3H), 5.73 (dd, J=15, 6 Hz, 1H), 5.55 (dd,
J=15, 9 Hz, 1H), 4.5–4.4 (m, 1H), 4.1–4.0 (m, 1H), 3.76
(s, 3H), 3.73 (s, 3H), 3.22 (s, 2H), 3.25–3.15 (m, 1H),
3.0–2.5 (m, 8H), 2.32 (s, 3H), 2.20 (s, 3H), 1.9–1.7 (m,
2H).
Methyl 9-acetoxy-11,15-dihydroxy-16-[3-(5-methoxyme-
thyl)thienyl]-!-tetranor-3,7-dithiaprosta-8,13-dienoate
17-15e. 22% yield; H NMR (200 MHz, CDCl3) d 7.23
(s, 1H), 7.08 (dd, J=8, 2Hz, 1H), 6.86 (d, J=8 Hz, 1H),
1

1004
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
5.75 (dd, J=16, 6 Hz, 1H), 5.56 (dd, J=16, 8 Hz, 1H),
4.4–4.25 (m, 1H), 4.15–4.05 (m, 1H), 3.89 (s, 3H), 3.74
(s, 3H), 3.3–3.2 (m, 1H), 3.23 (s, 3H), 2.95 (ddd, J=17,
6, 2 Hz, 1H), 2.8–2.5 (m, 7H), 2.46 (dd, J=17, 3 Hz,
1H), 2.38 (d, J=7 Hz, 1H), 2.21 (s, 3H), 1.9–1.7 (m,
3H).
1439, 1245, 1119, 1083, 1025, 759 cmÀ1 1H NMR
;
(200 MHz, CDCl3) d 7.32–7.08 (m, 2H), 7.00–6.85 (m,
2H), 5.87–5.52 (m, 2H), 4.68–3.90 (m, 2H), 3.87 (s, 3H),
3.66–2.12 (1m, 5H), 1.98–1.78 (m, 2H); MS (APCI) m/z
439 (MÀH)À.
16-(3-Methoxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6g.
70% yield; IR (neat) 3402, 2921, 1733, 1602, 1490,
1437, 1260, 1153, 1081, 1042, 971, 912, 785, 735,
16-(2-Methyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-6a. A
mixture of 12-6a (32mg, 0.063 mmol) and Amano PS
(100 mg) in dimethylsulfoxide (2mL) and phosphate
buffer (pH7.4, 2mL) was vigorously stirred for 3 h at
room temperature. After the hydrolysis was completed,
porcine liver esterase (PLE, Sigma, 20,000 U, 0.1 mL)
was added and the mixture was stirred for an additional
1 h. The resulting mixture was poured into saturated
aqueous (NH4)2SO4 and shaken with EtOAc. The
insoluble substances were removed by filtration through
a pad of Celite. The filtrate was separated and the aqu-
eous layer was extracted with EtOAc. The combined
organic layer was dried over Na2SO4 and evaporated.
The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 3/1 to EtOAc/AcOH, 50/1) to
afford 13-6a as a colorless oil (23 mg, 83%). IR (neat)
3600–3200, 2922, 1732, 1494, 1417, 1261, 1151, 1082,
1
698 cmÀ1; H NMR (200 MHz, CDCl3) d 7.3–7.2(m,
1H), 6.85–6.75 (m, 3H), 5.9–5.75 (m, 1H), 5.61 (dd,
J=15, 8 Hz, 1H), 4.5–4.3 and 4.1–3.9 (m, 2H), 3.79 (s,
3H), 3.7–3.2 (br), 3.22 (s, 2H), 3.4–3.3 and 3.0–2.2 (m,
10H), 2.0–1.8 (m, 2H); MS (APCI) m/z 439 (MÀH)À.
16-(4-Methoxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6h.
72% yield; IR (neat) 3392, 2917, 1732, 1514, 1246,
1083, 1032, 826, 732 cmÀ1; 1H NMR (200 MHz, CDCl3)
d 7.15 (d, J=8 Hz, 2H), 6.86 (d, J=8 Hz, 2H), 5.9–5.75
(m, 1H), 5.62(ss, J=16, 8 Hz, 1H), 4.5–4.3 and 4.2–4.0
(m, 2H), 3.22 (s, 2H), 3.4–2.7 (br), 3.4–3.3 and 3.0–2.3
(m, 10H), 2.0–1.8 (m, 2H); MS (APCI) m/z 439
(MÀH)À.
1
973, 850, 747, 669 cmÀ1; H NMR (200 MHz, CDCl3) d
16-(3-Ethoxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6i.
66% yield; IR (neat) 3392, 2926, 1732, 1601, 1584,
7.21–7.10 (m, 4H), 5.95–5.56 (m, 2H), 4.56–4.36 (m,
1H), 4.20–4.00 (m, 1H), 3.40–2.26 (1m, 8H), 1.98–1.78
(m, 2H); MS (APCI) m/z 423 (MÀH)À.
1
1489, 1257, 1050 cmÀ1; H NMR (200 MHz, CDCl3) d
7.27–7.17 (m, 1H), 6.80–6.76 (m, 3H), 5.87–5.53 (m,
2H), 4.80–4.40 (br, 4H), 4.14–4.00 (m, 1H), 4.02 (q,
J=7.0 Hz, 2H), 3.38–2.18 (m, 10H), 3.22 (s, 2H), 1.92–
1.78 (m, 2H), 1.41 (t, J=7.0 Hz, 3H); MS (APCI) m/z
453 (MÀH)À.
16-(3-Methyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-6b.
87% yield; IR (neat) 3391, 2919, 2248, 1731, 1609,
1488, 1417, 1266, 1147, 1081, 1036, 971, 911, 786, 734,
1
702cm À1; H NMR (200 MHz, CDCl3) d 7.25–7.0 (m,
4H), 5.9–5.5 (m, 2H), 4.5–4.0 (m, 2H), 3.8–3.6 (br), 3.22
(s, 2H), 3.4–2.2 (m, 10H), 2.33 (s, 3H), 2.0–1.8 (m, 2H);
MS (APCI) m/z 423 (MÀH)À.
16-(4-Ethoxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6j.
95% yield; IR (neat) 3392, 2919, 1732, 1613, 1583,
1511, 1299, 1245, 1047 cmÀ1 1H NMR (200 MHz,
;
CDCl3) d 7.12(d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz,
2H), 5.87–5.54 (m, 2H), 4.46–4.32 (m, 1H), 4.40–3.65
(4H, br), 4.01 (2H, q, J=7.0 Hz), 3.39–2.20 (m, 10H),
3.22 (s, 2H), 1.94–1.80 (m, 2H), 1.40 (t, J=7.0 Hz, 3H);
MS (APCI) m/z 453 (MÀH)À.
16-(4-Methyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-6c.
85% yield; IR (neat) 3392, 2920, 1729, 1417, 1263,
1
1115, 910, 806, 732cm À1; H NMR (200 MHz, CDCl3)
d 7.2–7.0 (m, 4H), 5.84 (dd, J=15, 5 Hz, 1H), 5.63 (dd,
J=15, 8 Hz, 1H), 4.5–4.3 (m, 1H), 4.2–4.0 (m, 1H), 3.5–
2.8 (br), 3.21 (s, 2H), 3.4–3.3 and 3.0–2.3 (m, 10H), 2.32
(s, 3H), 2.0–1.8 (m, 2H); MS (EI) m/z 406 (MÀH2O)+.
16-(3-Methylthio)phenyl-!-tetranor-3,7-dithiaPGE1 13-6k.
96% yield; IR (neat) 3392, 2921, 1732, 1593, 1573,
1476, 1421, 1266, 1147, 1084, 1028, 970, 909, 783, 730,
1
16-(3-Chloro)phenyl-!-tetranor-3,7-dithiaPGE1 13-6d.
90% yield; IR (neat) 3392, 2920, 2650, 2250, 1731,
1599, 1574, 1478, 1429, 1262, 1147, 1081, 1029, 971,
702cm À1; H NMR (200 MHz, CDCl3) d 7.24 (m, 1H),
7.12 (m, 2H), 6.99, (m, 1H), 5.9–5.5 (m, 2H), 4.43 (m,
1H), 4.03 (m, 1H), 4.0–3.6 (br), 3.22 (s, 2H), 3.4–2.1 (m,
10H), 2.48 (s, 3H), 2.0–1.8 (m, 2H); MS (APCI) m/z 455
(MÀH)À.
1
910, 784, 731, 704, 685, 649 cmÀ1; H NMR (200 MHz,
CDCl3) d 7.3–7.0 (m, 4H), 5.9–5.5 (m, 2H), 4.44 (m,
1H), 4.07 (m, 1H), 3.6–3.4 (br), 3.23 (s, 2H), 3.4–2.2 (m,
10H), 2.0–1.8 (m, 2H); MS (APCI) m/z 443 (MÀH)À.
16-(4-Methylthio)phenyl-!-tetranor-3,7-dithiaPGE1 13-6l.
96% yield; IR (neat) 3391, 2920, 1731, 1495, 1417,
;
1266, 1148, 1085, 1027, 970, 911, 805, 732 cmÀ1 1H
NMR (200 MHz, CDCl3) d 7.22 (d, J=9 Hz, 2H), 7.14
(d, J=9 Hz, 2H), 5.9–5.55 (m, 2H), 4.43 (m, 1H), 4.06
(m, 1H), 3.22 (s, 2H), 3.4–2.2 (m, 13H), 2.47 (s, 3H),
2.0–1.8 (m, 2H); MS (APCI) m/z 455 (MÀH)À.
16-(4-Chloro)phenyl-!-tetranor-3,7-dithiaPGE1 13-6e.
51% yield; IR (neat) 3391, 2922, 1730, 1408, 1271,
1
1087, 733 cmÀ1; H NMR (200 MHz, CDCl3) d 7.28 (d,
J=8 Hz, 2H), 7.16 (d, J=8 Hz, 2H), 5.9–5.7 (m, 1H),
5.62(dd, J=15, 8 Hz, 1H), 4.5–4.4 (m, 1H), 4.2–4.0 (m,
1H), 3.22 (s, 2H), 3.4–2.8 (br), 3.4–3.3 and 3.0–2.3 (m,
10H), 2.0–1.8 (m, 2H); MS (APCI) m/z 443 (MÀH)À.
16-(3-Hydroxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6m
.
49% yield; IR (neat) 3600-3200, 2985, 2936, 1736,
1589, 1455, 1375, 1245, 1158, 1046, 849, 787, 699, 636,
;
610 cmÀ1 1H NMR (200 MHz, CD3OD) d 7.15–7.02
16-(2-Methoxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6f.
51% yield; IR (neat) 3600–3200, 2919, 1730, 1494,

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
1005
(m, 1H), 6.78–6.56 (m, 3H), 5.74 (dd, J=15.4, 5.8 Hz,
1H), 5.67–5.51 (m, 1H), 4.38–4.23 (m, 1H), 4.11–3.95
(m, 1H), 3.50–2.06 (m, 2H), 1.97–1.72 (m, 2H); MS
(APCI) m/z 425 (MÀH)À.
16-(3-Methoxyethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7c. 87% yield; IR (neat) 3392, 2921, 1732, 1608,
1488, 1446, 1265, 1084 cmÀ1 1H NMR (200 MHz,
;
CDCl3) d 7.30–7.01 (m, 4H), 5.80 (dd, J=15.4, 5.8 Hz,
1H), 5.60 (dd, J=15.4, 8.0 Hz, 1H), 5.50–4.60 (br, 3H),
4.47–4.28 (m, 1H), 4.06–3.96 (m, 1H), 3.65 (t, J=6.6 Hz,
2H), 3.35 (s, 3H), 3.21 (s, 2H), 3.00–2.18 (1m, 2H), 1.93–
1.80 (m, 2H); MS (APCI) m/z 467 (MÀH)À.
16-(4-Hydroxy)phenyl-!-tetranor-3,7-dithiaPGE1 13-6n.
48% yield; IR (neat) 3368, 2919, 1730, 1614, 1515,
1445, 1245 cmÀ1; 1H NMR (200 MHz, CDCl3) d 7.05 (d,
J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 5.73 (dd,
J=15.4, 6.2Hz, 1H), 5.56 (dd, J=15.4, 7.4 Hz, 1H),
4.95–4.80 (4H, br), 4.38–4.19 (m, 1H), 4.10–3.98 (m,
1H), 3.48–2.15 (m, 10H), 3.22 (s, 2H), 1.91–1.78 (m,
2H); MS (APCI) m/z 425 (MÀH)À.
16-(3-Methoxypropyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7d. 73% yield; IR (neat) 3600–3200, 2923, 1732,
1608, 1446, 1417, 1255, 1083, 1046, 971, 757, 706,
1
667 cmÀ1; H NMR (200 MHz, CDCl3) d 7.30–6.97 (m,
4H), 5.90–5.68 (m, 1H), 5.60 (dd, J=15.4, 8.0 Hz, 1H),
5.50–5.00 (br, 3H), 4.52–4.28 (m, 1H), 4.13–3.94 (m,
1H), 3.42(t, J=6.4 Hz, 2H), 3.35 (s, 3H), 3.21 (s, 2H),
3.04–2.13 (1m, 2H), 1.99–1.76 (m, 4H); MS (APCI) m/z
481(MÀH)À.
16-(3-Methylsulfonyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-6o. 44% yield; IR (neat) 3391, 2924, 1732, 1417,
1
1296, 1143 cmÀ1; H NMR (200 MHz, CDCl3) d 7.85–
7.76 (m, 2H), 7.64–7.50 (m, 2H), 5.83–5.50 (m, 2H),
4.43–3.99 (m, 2H), 3.49–2.12 (m, 10H), 3.22 (s, 2H),
3.12(s, 3H), 1.93–1.78 (m, 2H); MS (APCI) m/z 487
(MÀH)À.
16-(3-Ethoxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7e. 56% yield; IR (neat) 3600-3200, 2976, 2927,
1732, 1445, 1417, 1375, 1250, 1158, 1084, 1046, 972,
;
757, 705, 667 cmÀ1 1H NMR (200 MHz, CDCl3) d
7.35–7.10 (m, 4H), 5.91–5.47 (m, 2H), 4.60–3.50 (m,
9H), 3.38–2.10 (1m, 2H), 1.96–1.76 (m, 2H), 1.25 (3H, t,
J=6.9 Hz); MS (APCI) m/z 467 (MÀH)À.
16-(4-Methylsulfonyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-6p. 79% yield; IR (neat) 3418, 2924, 2639, 1732,
1598, 1411, 1295, 1147, 1088, 1035, 966, 766, 669,
1
534 cmÀ1; H NMR (200 MHz, CDCl3) d 7.86 (m, 2H),
7.52 (m, 2H), 5.69 (m, 2H), 4.36 (m, 1H) 4.05 (m, 1H),
3.52–2.08 (m, 10H), 3.23 (s, 2H), 3.10 (s, 3H), 2.0–1.8
(m, 2H); MS (APCI) m/z 487 (MÀH)À.
16-(3-Propoxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7f. 88% yield; IR (neat) 3392, 2927, 2874, 1733,
1417, 1362, 1262, 1157, 1083, 1038, 970, 910, 772, 733,
1
16-(3-Methoxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-6q. 72% yield; IR (neat) 3392, 2922, 1730, 1265, 1193,
705 cmÀ1; H NMR (200 MHz, CDCl3) d 7.37–7.10 (m,
4H), 5.89–5.48 (m, 2H), 4.58–3.87 (m, 2H), 4.48 (s, 2H),
4.42(3H, br), 3.49 (t, J=7 Hz, 2H), 3.21 (s, 2H), 3.38–
2.14 (m, 10H), 1.9–1.7 (m, 2H), 1.7–1.6 (m, 2H), 0.94 (t,
J=7 Hz, 3H); MS (APCI) m/z 481 (MÀH)À.
1157, 1084, 971, 912, 732, 705 cmÀ1
;
1H NMR
(200 MHz, CDCl3) d 7.35–7.10 (m, 4H), 5.9–5.5 (m,
2H), 4.6–4.4 (m, 3H), 4.43 (s, 2H), 4.4–4.3 and 4.05–3.9
(m, 1H), 3.8–3.1 (br, 3H), 3.42and 3.41 (s, 3H), 3.22(s,
2H), 3.4–3.3 and 3.0–2.2 (m, 10H), 2.0–1.8 (m, 2H); MS
(APCI) m/z 453 (MÀH)À.
16-(3-Allyloxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7g. 79% yield; IR (neat) 3600-3200, 2921, 1732, 1418,
;
1347, 1265, 1157, 1080, 933, 793, 758, 705 cmÀ1 1H
16-(4-Methoxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-6r. 75% yield; IR (neat) 3392, 2921, 1732, 1417, 1270,
NMR (200 MHz, CDCl3) d 7.37–7.09 (m, 4H), 6.07–
5.18 (m, 8H), 4.62–3.86 (m, 6H), 3.40–2.12 (1m, 2H),
1.96–1.74 (m, 2H); MS (APCI) m/z 479 (MÀH)À.
1
1084, 971, 911, 733 cmÀ1; H NMR (200 MHz, CDCl3)
d 7.35–7.15 (m, 4H), 5.9–5.5 (m, 2H), 4.5–4.4 (m, 3H),
4.4–4.3 and 4.1–3.9 (m, 1H), 4.0–3.5 (br, 3H), 3.42(m,
3H), 3.22 (s, 2H), 3.4–3.3 and 3.0–2.2 (m, 10H), 2.0–1.8
(m, 2H); MS (APCI) m/z 453 (MÀH)À.
16-(3-Isopropoxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7h. 72% yield; IR (neat) 3392, 2927, 1733, 1383,
1262, 1125, 1073, 912, 793, 733 cmÀ1
;
1H NMR
(200 MHz, CDCl3) d 7.3–7.1 (m, 4H), 5.9–5.5 (m, 2H),
4.6–4.4 (m, 3H), 4.4–4.25 and 4.0–3.9 (m, 1H), 3.85–
3.65 (m, 1H), 3.6–3.2 (br, 3H), 3.22 (s, 2H), 3.4–3.3 and
3.0–2.2 (m, 10H), 2.0–1.8 (m, 2H), 1.3–1.2 (m, 6H); MS
(APCI) m/z 481 (MÀH)À.
16-(3-Hydroxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7a. 49% yield; IR (neat) 3392, 2921, 1732, 1417, 1261,
1153, 1082, 1040, 901, 792, 705 cmÀ1
;
1H NMR
(200 MHz, CDCl3) d 7.31–7.09 (m, 4H), 5.75 (dd, J=15,
6.2Hz, 1H), 5.59 (dd, J=15, 7.3 Hz, 1H), 4.58 (s,
2H), 4.32 (m, 1H), 4.02 (m, 1H), 3.22 (s, 2H), 3.49–
2.08 (m, 10H), 1.9–1.7 (m, 2H); MS (APCI) m/z 439
(MÀH)À.
16-(3-Phenoxymethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7i. 85% yield; IR (neat) 3392, 2921, 1731, 1599,
1
1494, 1383, 1240, 1080, 1035, 792, 758, 695 cmÀ1; H
NMR (200 MHz, CDCl3) d 7.38–7.13 (m, 6H), 6.97 (m,
3H), 5.88–5.52 (m, 2H), 5.03 (s, 2H), 4.53–3.90 (m, 2H),
4.6–4.2 (br), 3.20 (s, 2H), 3.38–2.12 (m, 10H), 2.0–1.8
(m, 2H); MS (APCI) m/z 515 (MÀH)À.
16-(3-Methylthiomethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-7b. 76% yield; IR (neat) 3600–3200, 2917, 1732, 1424,
1
1375, 1249, 1148, 1083, 1046, 972, 757, 707 cmÀ1; H
NMR (200 MHz, CDCl3) d 7.35–7.05 (m, 4H), 5.92–
5.56 (m, 2H), 4.58–3.96 (m, 2H), 3.88–2.10 (1m, 7H),
2.04–2.02 (m, 3H), 1.98–1.78 (m, 2H); MS (APCI) m/z
469 (MÀH)À.
16-(3-Cyclohexyloxymethyl)phenyl-!-tetranor-3,7-di-
thiaPGE1 13-7j. 81% yield; IR (neat) 3600–3200, 2932,
2857, 1732, 1449, 1374, 1246, 1155, 1082, 970, 791, 757,

1006
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
705, 667 cmÀ1; 1H NMR (200 MHz, CDCl3) d 7.34–7.08
(m, 4H), 5.90–5.46 (m, 2H), 5.10–4.60 (br, 3H), 4.60–
3.70 (m, 4H), 3.50–3.28 (m, 1H), 3.20 (s, 2H), 3.14–2.24
(m, 10H), 2.10–1.10 (1m, 2H); MS (APCI) m/z 521
(MÀH)À
(m, 1H), 3.21 (s, 2H), 3.07–2.20 (m, 2H), 1.92–1.89–1.69
(m, 2H); MS (APCI) m/z 455 (MÀH)À.
16-[3-(1-Propynyl)]phenyl-!-tetranor-3,7-dithiaPGE1 13-8g.
74% yield; IR (neat) 3392, 2917, 1728, 1418, 1265,
1147, 1081, 971, 910, 793, 731 cmÀ1
;
1H NMR
16-[3-(1-Methoxyethyl)]phenyl-!-tetranor-3,7-dithiaPGE1
13-7k. 78% yield; IR (neat) 3392, 2927, 1731, 1446,
(200 MHz, CDCl3) d 7.3–7.1 (m, 4H), 5.9–5.5 (m, 2H),
4.5–4.35 and 4.1–4.0 (m, 2H), 3.9–3.2 (br, 3H), 3.22 (s,
2H), 3.4–3.3 and 3.0–2.3 (m, 10H), 2.04 (s, 3H), 2.0–1.8
(m, 2H); MS (APCI) m/z 447 (MÀH)À.
1
1261, 1083, 913, 797, 735 cmÀ1; H NMR (200 MHz,
CDCl3) d 7.35–7.1 (m, 4H), 5.9–5.5 (m, 2H), 4.65–4.45
(m, 1H), 4.4–4.25 (m, 1H), 4.1–3.9 (m, 1H), 4.2–3.4 (br,
3H), 3.27 and 3.26 (s, 3H), 3.22 (s, 2H), 3.4–3.3 and
3.05–2.3 (m, 8H), 2.0–1.8 (m, 2H), 1.45 (d, J=7 Hz,
3H); MS (APCI) m/z 467 (MÀH)À.
16-[3-(2-Phenylethynyl)]phenyl-!-tetranor-3,7-dithiaPGE1
13-8h. 81% yield; IR (neat) 3600–3200, 2922, 1732,
1602, 1494, 1443, 1418, 1278, 1217, 1148, 1082, 1027,
1
971, 757, 692, 668 cmÀ1; H NMR (200 MHz, CDCl3) d
16-(3-Ethyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-8a. 36%
yield; IR (neat) 3600–3200, 2964, 2928, 1731, 1607,
1488, 1417, 1375, 1255, 1148, 1082, 1046, 971, 798, 757,
7.60–7.11 (m, 9H), 5.89–5.67 (m, 1H), 5.57 (dd, J=15.4,
8.0 Hz, 1H), 4.94–4.30 (m, 4H), 4.12–3.93 (m, 1H),
3.42–2.12 (1m, 2H), 1.95–1.72 (m, 2H); MS (APCI) m/z
509 (MÀH)À.
1
705 cmÀ1; H NMR (200 MHz, CDCl3) d 7.30–6.96 (m,
4H), 5.90–5.55 (m, 2H), 4.43–4.30 (m, 1H), 4.14–3.96
(m, 1H), 3.90–3.41 (br, 3H), 3.41–2.16 (m, 4H), 1.96–
1.78 (m, 2H), 1.23 (t, J=7.5 Hz, 3H); MS (APCI) m/z
437 (MÀH)À.
16-(3-Phenyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-8i.
63% yield; IR (neat) 3600-3200, 2921, 1731, 1715,
1600, 1481, 1417, 1374, 1256, 1153, 1078, 1046, 972,
;
760, 729, 703 cmÀ1 1H NMR (200 MHz, CDCl3) d
16-(3-Vinyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-8b. 55%
yield; IR (neat) 3600–3200, 2984, 2927, 1732, 1375,
1245, 1153, 1082, 1046, 972, 912, 800, 758, 717 cmÀ1; 1H
NMR (200 MHz, CDCl3) d 7.37–7.05 (m, 4H), 6.68 (1H,
dd, J=17.8, 10.8 Hz), 5.92–5.50 (m, 3H), 5.44–4.70 (m,
4H), 4.54–3.92 (m, 2H), 3.40–2.10 (m, 2H), 1.96–1.74
(m, 2H); MS (APCI) m/z 435 (MÀH)À.
7.64–7.14 (m, 9H), 5.95–5.57 (m, 2H), 4.64–3.92 (m,
2H), 3.40–2.08 (1m, 5H), 1.96–1.74 (m, 2H); MS (APCI)
m/z 485 (MÀH)À.
16-[3-(2-Thienyl)]phenyl-!-tetranor-3,7-dithiaPGE1 13-8j.
51% yield; IR (neat) 3600–3200, 2922, 1732, 1605,
1483, 1443, 1424, 1375, 1251, 1148, 1082, 1046, 971,
;
789, 757, 703 cmÀ1 1H NMR (200 MHz, CDCl3) d
16-(3-Propyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-8c.
80% yield; IR (neat) 3392, 2928, 1732, 1417, 1261,
7.55–7.40 (m, 2H), 7.36–7.22 (m, 3H), 7.15–7.02 (m,
2H), 5.88–5.69 (m, 1H), 5.56 (dd, J=15.4, 8.0 Hz, 1H),
5.14–4.55 (br, 3H), 4.50–4.27 (m, 1H), 4.09–3.90 (m,
1H), 3.37–2.12 (m, 2H), 1.92–1.70 (m, 2H); MS (APCI)
m/z 491 (MÀH)À.
1080, 909, 787, 732, 705 cmÀ1 1H NMR (200 MHz,
;
CDCl3) d 7.3–7.0 (m, 4H), 5.9–5.6 (m, 2H), 4.55–4.3 and
4.1–4.0 (m, 1H), 3.6–3.0 (br, 3H), 3.22 (s, 2H), 3.4–3.3
and 3.0–2.2 (m, 12H), 2.0–1.8 (m, 2H), 1.75–1.55 (m,
2H), 0.94 (t, J=7 Hz, 3H); MS (APCI) m/z 451
(MÀH)À.
16-[3-(2-Furyl)]phenyl-!-tetranor-3,7-dithiaPGE1 13-8k.
90% yield; IR (neat) 3398, 2920, 2361, 1731, 1611,
1419, 1289, 1154, 1079, 1015, 910, 791, 734, 700 cmÀ1
;
16-(3-Isopropyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-8d.
78% yield; IR (neat) 3392, 2960, 1733, 1418, 1262,
1082, 970, 912, 794, 731, 707 cmÀ1; 1H NMR (200 MHz,
CDCl3) d 7.3–7.0 (m, 4H), 5.9–5.6 (m, 2H), 4.55–4.4 and
4.2–4.0 (m, 2H), 4.2–3.8 (br, 3H), 3.22 (s, 2H), 3.4–3.3
and 3.0–2.2 (m, 11H), 2.0–1.8 (m, 2H), 1.24 (d, J=7 Hz,
6H); MS (APCI) m/z 451 (MÀH)À.
1H NMR (200 MHz, CDCl3) d 7.6–7.5 (m, 2H), 7.47 (d,
J=1.9 Hz, 1H), 7.32(t, J=7.9 Hz, 1H), 7.10 (d,
J=7.9 Hz, 1H), 6.66 (d, J=3.4 Hz, 1H), 6.47 (dd,
J=3.4, 1.9 Hz, 1H), 5.91–5.53 (m, 2H), 4.56–3.94 (m,
2H), 4.0–3.6 (br), 3.21 (s, 2H), 3.39–2.13 (m, 10H), 1.9–
1.7 (m, 2H); MS (APCI) m/z 475 (MÀH)À.
16-(3-Cyano)phenyl-!-tetranor-3,7-dithiaPGE1 13-8l.
61% yield; IR (neat) 3413, 2924, 2230, 1730, 1417,
16-(3-Benzyl)phenyl-!-tetranor-3,7-dithiaPGE1 13-8e.
47% yield; IR (neat) 3391, 3026, 2919, 1732, 1601,
1494, 1445, 1265, 1147, 1077, 1030, 970, 910, 733,
1
1265, 1149, 1081, 1031, 972, 913, 732 cmÀ1; H NMR
(200 MHz, CDCl3) d 7.6–7.4 (m, 4H), 5.85–5.5 (m, 2H),
4.45–4.3 and 4.1–3.95 (m, 2H), 3.22 (s, 2H), 3.4–3.35
and 3.0–2.2 (m, 13H), 2.0–1.8 (m, 2H); MS (APCI) m/z
434 (MÀH)À.
1
707 cmÀ1; H NMR (200 MHz, CDCl3) d 7.34–6.99 (m,
9H), 5.84–5.49 (m, 2H), 5.0–4.6 (br), 4.39 (m, 1H), 3.97
(m, 1H), 3.94 (s, 2H), 3.19 (s, 2H), 3.37–2.22 (m, 10H),
1.9–1.7 (m, 2H); MS (APCI) m/z 499 (MÀH)À.
16-(3-Trifluoromethyl)phenyl-!-tetranor-3,7-dithiaPGE1
13-8m. 73% yield; IR (neat) 3600–3200, 2927, 1732,
1450, 1376, 1331, 1251, 1163, 1124, 1075, 1046, 971,
801, 705 cmÀ1; 1H NMR (200 MHz, CDCl3) d 7.57–7.38
(m, 4H), 5.91–5.57 (m, 2H), 4.54–3.98 (m, 2H), 3.46–
2.14 (1m, 5H), 1.97–1.78 (m, 2H); MS (APCI) m/z 477
(MÀH)À.
16-[3-(2-Fluoroethyl)]phenyl-!-tetranor-3,7-dithiaPGE1
13-8f. 88% yield; IR (neat) 3392, 2918, 1732, 1609,
1489, 1417, 1261, 1148, 1080 cmÀ1; 1H NMR (200 MHz,
CDCl3) d 7.32–7.04 (m, 4H), 5.79 (dd, J=15.4, 6.2Hz,
1H), 5.59 (dd, J=15.4, 8.2Hz, 1H), 5.50–4.90 (br, 3H),
4.62(dt, J=7.0 Hz, 2H), 4.47–4.29 (m, 1H), 4.10–3.96

T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
1007
16-(3,4-Dichloro)phenyl-!-tetranor-3,7-dithiaPGE1 18-14a.
77% yield; IR (neat) 3600–3200, 2927, 1731, 1713,
1422, 1259, 1213, 1167, 1089, 1008, 911, 771, 732 cmÀ1
;
1H NMR (200 MHz, CDCl3) d 7.2–7.0 (m, 3H), 5.76
(dd, J=16, 5 Hz, 1H), 5.52(dd, J=16, 8 Hz, 1H), 4.7–
4.5 (m, 1H), 4.3–4.2and 4.0–3.8 (m, 1H), 4.4–3.4 (br,
3H), 3.78 (s, 3H), 3.22 (s, 2H), 3.3–3.2 and 3.1–2.3 (m,
10H), 2.30 (s, 3H), 1.95–1.8 (m, 2H); MS (APCI) m/z
453 (MÀH)À.
1472, 1395, 1260, 1133, 1082, 1032, 972, 896, 820 cmÀ1
;
1H NMR (200 MHz, CDCl3) d 7.38 (d, J=8.4 Hz, 1H),
7.34 (d, J=1.8 Hz, 1H), 7.07 (dd, J=8.4, 1.8 Hz, 1H),
5.92–5.54 (m, 2H), 4.53–4.32 (m, 1H), 4.20–4.00 (m,
1H), 3.44–2.12 (1m, 5H), 1.98–1.80 (m, 2H); MS (APCI)
m/z 477 (MÀH)À.
16-(2,3-Dimethyl)phenyl-!-tetranor-3,7-dithiaPGE1 18-14i.
83% yield; IR (neat) 3392, 2921, 1731, 1261, 1077, 910,
16-(3,4-Dimethoxy)phenyl-!-tetranor-3,7-dithiaPGE1
18-14b. 29% yield; IR (neat) 3600–3200, 2932, 1732,
1
781, 730 cmÀ1; H NMR (200 MHz, CDCl3) d 7.1–7.0
1
1516, 1465, 1418, 1261, 1141, 1029, 809, 758 cmÀ1; H
(m, 3H), 5.9–5.6 (m, 2H), 4.5–4.4 (m, 1H), 4.2–4.0 (m,
1H), 3.8–3.0 (br, 3H), 3.22 (s, 2H), 3.4–3.35 and 3.0–2.3
(m, 10H), 2.28 (s, 3H), 2.24 (s, 3H), 2.0–1.8 (m, 2H); MS
(APCI) m/z 437 (MÀH)À.
NMR (200 MHz, CDCl3) d 6.88–6.72(m, 3H), 5.93–
5.58 (m, 2H), 4.54–4.00 (m, 2H), 3.88 (s, 3H), 3.86 (s,
3H), 3.60–2.16 (1m, 5H), 1.98–1.78 (m, 2H); MS (APCI)
m/z 469 (MÀH)À.
16-(3,5-Dimethyl)phenyl-!-tetranor-3,7-dithiaPGE1 18-14j
37% yield; IR (neat) 3600–3200, 2919, 1730, 1606,
1417, 1294, 1148, 1083, 1037, 971, 842, 757, 710 cmÀ1
1H NMR (200 MHz, CDCl3) d 6.88 (brs, 1H), 6.83 (br2,
2H), 5.91–5.58 (m, 2H), 4.55–4.30 (m, 1H), 4.16–3.96
(m, 1H), 3.42–2.32 (m, 5H), 2.29 (s, 6H), 1.99–1.78 (m,
2H); MS (APCI) m/z 437 (MÀH)À.
.
16-(3-Chloro-4-methoxy)phenyl-!-tetranor-3,7-dithiaPGE1
18-14c. 72% yield; IR (neat) 3392, 2920, 1732, 1504,
;
1441, 1257, 1148, 1065, 1024, 972, 908, 811, 732 cmÀ1
;
1H NMR (200 MHz, CDCl3) d 7.24 (d, J=2Hz, 1H),
7.08 (dd, J=8, 2Hz, 1H), 6.88 (d, J=8 Hz, 1H), 5.81
and 5.79 (dd, J=15, 5 Hz, 1H), 5.72and 5.62(dd,
J=15, 8 Hz, 1H), 4.45–4.4 and 4.1–4.05 (m, 2H), 3.89 (s,
3H), 3.7–2.8 (br, 3H), 3.22 (s, 3H), 3.38 and 3.0–2.5 (m,
9H), 2.42 (dd, J=19, 10 Hz), 2.26 (dd, J=19, 7 Hz),
1.9–1.8 (m, 2H); MS (APCI) m/z 473 (MÀH)À.
16-(3-Methoxy-5-methyl)phenyl-!-tetranor-3,7-dithiaPGE1
18-14k. 85% yield; IR (neat) 3392, 2920, 1736, 1596,
;
1460, 1294, 1153, 1069, 970, 912, 836, 732 cmÀ1 1H
NMR (200 MHz, CDCl3) d 6.65–6.55 (m, 3H), 5.9–5.6
(m, 2H), 4.5–4.3 and 4.1–4.0 (m, 2H), 3.79 (s, 3H), 3.7–
3.0 (br, 3H), 3.22 (s, 2H), 3.4–3.3 and 3.0–2.3 (m, 10H),
2.32 (s, 3H), 2.0–1.8 (m, 2H); MS (APCI) m/z 453
(MÀH)À.
16-(3-Methyl-4-methoxy)phenyl-!-tetranor-3,7-dithiaPGE1
18-14d. 84% yield; IR (neat) 3392, 2919, 2248, 1732,
1614, 1505, 1417, 1253, 1226, 1135, 1081, 1035, 972,
;
911, 811, 733 cmÀ1 1H NMR (200 MHz, CDCl3) d
7.05–6.95 (m, 2H), 6.76 (d, J=9.0 Hz, 1H), 5.90–5.55
(m, 2H), 4.40 (m, 1H), 4.06 (m, 1H), 4.3–3.7 (br), 3.81
(s, 3H), 3.21 (s, 2H), 3.41–2.27 (m, 10H), 2.20 (s, 3H),
2.0–1.8 (m, 2H); MS (APCI) m/z 453 (MÀH)À.
16-(2-Naphthyl)-!-tetranor-3,7-dithiaPGE1 18-15a. 37%
yield; IR (neat) 3600–3200, 2927, 1732, 1715, 1374,
1
1246, 1078, 1046, 971, 820, 754, 735 cmÀ1; H NMR
(200 MHz, CDCl3) d 7.87–7.28 (m, 7H), 5.96–5.46 (m,
2H), 4.66–3.88 (m, 2H), 3.60–2.10 (1m, 5H), 1.92–1.70
(m, 2H); MS (APCI) m/z 459 (MÀH)À.
16-(3-Methyl-4-hydroxy)phenyl-!-tetranor-3,7-dithiaPGE1
18-14e. 72% yield; IR (neat) 3392, 2920, 1732, 1715,
1614, 1509, 1423, 1265, 1151, 1120, 1081, 1043, 972,
1
820, 782 cmÀ1; H NMR (200 MHz, CD3OD) d 6.9–6.8
16-(5-Isocoumaranyl)-!-tetranor-3,7-dithiaPGE1 18-15b.
82% yield; IR (neat) 3391, 2917, 2649, 2359, 1731,
1715, 1494, 1417, 1372, 1260, 1143, 1082, 1044, 972,
(m, 2H), 6.64 (d, J=8.0 Hz, 1H), 5.72(dd, J=15,
6.2Hz, 1H), 5.56 (dd, J=15, 7.8 Hz, 1H), 4.37–3.95 (m,
2H), 3.22 (s, 2H), 3.48–2.13 (m, 10H), 2.15 (s, 3H), 1.9–
1.7 (m, 2H); MS (APCI) m/z 439 (MÀH)À.
1
892, 822, 775, 707 cmÀ1; H NMR (200 MHz, CDCl3) d
7.2–7.0 (m, 3H), 5.73 (dd, J=15, 6.3 Hz, 1H), 5.58 (dd,
J=15, 7.6 Hz, 1H), 5.04 (s, 4H), 4.30 (m, 1H) 4.04 (m,
1H), 3.21 (s, 2H), 3.50–2.16 (m, 10H), 1.9–1.8 (m, 2H);
MS (APCI) m/z 451 (MÀH)À.
16-(3-Chloro-6-methoxyphenyl)-!-tetranor-3,7-dithiaPGE1
18-14f. 93% yield; IR (neat) 3392, 2921, 1732, 1489,
1248, 1130, 1081, 1029, 970, 910, 809, 773, 732 cmÀ1; 1H
NMR (200 MHz, CDCl3) d 7.2–7.1 (m, 2H), 6.82 (d,
J=8.8 Hz, 1H), 5.87–5.54 (m, 2H), 4.62–3.95 (m, 2H),
3.84 (s, 3H), 3.7–3.3 (br), 3.22 (s, 2H), 3.37–2.17 (m,
10H), 2.0–1.8 (m, 2H); MS (APCI) m/z 473 (MÀH)À.
16-(3-Thienyl)-!-tetranor-3,7-dithiaPGE1 18-15c. 75%
yield; IR (neat) 3392, 2918, 1732, 1417, 1262, 1147,
;
1080, 971, 911, 781, 730 cmÀ1 1H NMR (200 MHz,
CDCl3) d 7.30 (dd, J=5, 2Hz, 1H), 7.08 (d, J=2Hz,
1H), 6.98 (d, J=5 Hz, 1H), 5.9–5.75 (m, 1H), 5.65 (dd,
J=15, 8 Hz, 1H), 4.55–4.4 (m, 1H), 4.45–4.3 and 4.15–
4.0 (m, 1H), 3.22 (s, 2H), 3.4–3.35 and 3.2–2.2 (m, 13H),
2.0–1.8 (m, 2H); MS (APCI) m/z 415 (MÀH)À.
16-(2,5-Dimethylphenyl)-!-tetranor-3,7-dithiaPGE1 18-14g.
18% yield; IR (neat) 3600–3200, 2923, 1733, 1504,
1
1417, 1261, 1147, 1081, 1040, 971, 813, 757 cmÀ1; H
NMR (200 MHz, CDCl3) d 7.12–6.88 (m, 3H), 5.93–
5.56 (m, 2H), 4.52–3.80 (m, 5H), 3.42–2.14 (1m, 8H),
1.98–1.78 (m, 2H); MS (APCI) m/z 437 (MÀH)À.
16-(2-Thienyl)-!-tetranor-3,7-dithiaPGE1 18-15d. 73%
yield; IR (neat) 3600–3200, 2917, 1730, 1715, 1417,
1
1298, 1082, 1039, 851, 703 cmÀ1; H NMR (200 MHz,
16-(2-Methoxy-3-methylphenyl)-!-tetranor-3,7-dithiaPGE1
18-14h. 63% yield; IR (neat) 3402, 2926, 1730, 1471,
CDCl3) d 7.19 (dd, J=5.1, 1.2Hz, 1H), 6.97 (dd, J=5.1,
3.3 Hz, 1H), 6.92–6.85 (m, 1H), 5.91–5.58 (m, 2H),

1008
T. Maruyama et al. / Bioorg. Med. Chem. 10 (2002) 989–1008
4.58–4.32(m, 1H), 4.20–3.95 (m, 1H), 3.43–2.15 (1m,
5H), 1.98–1.78 (m, 2H); MS (APCI) m/z 415 (MÀH)À.
well). After 2days, the media were removed and cells
were washed with 500 mL of Minimum Essential Med-
ium (MEM) and preincubated for 10 min in 450 mL of
assay buffer (MEM containing 1 mM of IBMX, 1% of
BSA) at 37 ꢁC. Then reaction was started with the
addition of each test compound in 50 mL of assay buffer.
After incubation for 10 min at 37 ꢁC, the reaction was
terminated by addition of 500 mL of ice-cold 10% tri-
chloroacetic acid. The cAMP production was measured by
radioimmunoassay using a cAMP assay kit (Amersham).
16-[3-(5-Methoxymethyl)thienyl]-!-tetranor-3,7-dithiaPGE1
18-15e. 71% yield; IR (neat) 3392, 2921, 1728, 1418,
1
1263, 1079, 909, 808, 732 cmÀ1; H NMR (200 MHz,
CDCl3) d 6.85 (d, J=3 Hz, 1H), 6.74 (d, J=3 Hz, 1H),
5.9–5.6 (m, 2H), 4.55 (s, 2H), 4.55–4.35 and 4.1–3.9 (m,
2H), 4.3–3.5 (br, 3H), 3.40 (s, 3H), 3.22 (s, 2H), 3.4–3.35
and 3.1–2.3 (m, 10H), 2.0–1.8 (m, 2H); MS (APCI) m/z
459 (MÀH)À.
Prostanoid EP and IP receptor binding assay
Membranes from CHO cells expressing the prostanoid
receptors were incubated with radioligand (2.5 nM of
[3H]PGE2 for EP1-4 or 5.0 nM of [3H]Iloprost for IP)
and the test compounds at various concentrations in
assay buffer (10 mM Kpi (KH2PO4, KOH; pH 6.0),
1 mM EDTA and 0.1 mM NaCl, for EP1-4-receptors;
50 mM Tris–HCl (pH 7.5), 1 mM EDTA and 10 mM
MgCl2 for IP-receptor). Incubation was carried out at
25ꢁC for 60 min except for EP1 (20 min) and IP (30 min)
receptors. The incubation was terminated by filtration
through Whatman GF/B filters. The filters were then
washed with ice-cold buffer (10 mM Kpi (KH2PO4,
KOH; pH 6.0), 0.1 mM NaCl for EP1-4; 10 mM Tris–
HCl (pH 7.5), 0.1 mM NaCl for IP), and the radio-
activity on the filter was measured in 6 mL of liquid
scintillation (ACSII) mixture with a liquid scintillation
counter. Nonspecific binding was determined by incu-
bation of 10 mM unlabeled PGE2 (for EP1-4) or 1 mM
unlabeled Iloprost (for IP) with assay buffer.
References and Notes
1. (a) Willis, A. C. Ed. Handbook of Eicosanoids: Prosta-
glandins and Related Lipids, CRC: FL, 1987; Vol. 1, Part B.
(b) Roberts, S. M., Scheinmann, F., Eds. Chemistry, Bio-
chemistry and Pharmacological Activity of Prostanoids. Perga-
mon: Oxford, 1979.
2. Maruyama, T.; Asada, M.; Shiraishi, T.; Egashira, H.;
Yoshida, H.; Maruyama, T.; Ohuchida, S.; Nakai, H.; Kondo,
K.; Toda, M. Bioorg. Med. Chem. The preceding paper I.
3. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki,
H. Tetrahedron Lett. 1983, 24, 5281 See the review article:
Cintas, P. Synthesis 1992, 248.
4. Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L.;
Moretti, R.; Koerner, M.; Lipshutz, B. H. J. Am. Chem. Soc.
1988, 110, 2641.
5. Absolute configuration of 15-OH of the more polar isomers
was reconfirmed by their enantioselective synthesis starting
from (R)-(+)-glycidol. The synthesis will be reported in the
following paper.
6. Subtype selectivity of 13-6q (EC50EP3/EC50EP4) was
reconfirmed by measuring both EP3- and EP4-receptor ago-
nist activities.
Measurement of cAMP production
Chinese hamster ovary (CHO) cells expressing EP4-
receptor were cultured in 24-well plates (1 Â 105 cells/
7. Kiriyama, M.; Ushikubi, F.; Kobayashi, T.; Hirata, M.;
Sugimoto, Y.; Narumiya, S. Br. J. Pharmacol. 1997, 122, 217.