Discovery of thiochroman and chroman derivatives as pure antiestrogens and their structure-activity relationship

Article abstract of DOI:10.1016/j.bmc.2006.03.020

In order to develop pure antiestrogens, a series of 7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman and 7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman derivatives with sulfoxide containing side chains at the 4-position were designed, synthesized, and eva

Full text of DOI:10.1016/j.bmc.2006.03.020

Bioorganic & Medicinal Chemistry 14 (2006) 4803–4819
Discovery of thiochroman and chroman derivatives
as pure antiestrogens and their structure–activity relationship
Yoshitake Kanbe,a,* Myung-Hwa Kim,a Masahiro Nishimoto,a
Yoshihito Ohtake,a Nobuaki Kato,a Toshiaki Tsunenari,a Kenji Taniguchi,a
Iwao Ohizumi,a Shin-ichi Kaiho,a Kazumi Morikawa,a Jae-Chon Jo,b
Hyun-Suk Limb and Hak-Yeop Kimb
aFuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan
bC&C Research Laboratories, 146-141, Annyung, Taean, Hwasung, Kyunggi 445-976, Republic of Korea
Received 15 February 2006; revised 10 March 2006; accepted 13 March 2006
Available online 31 March 2006
Abstract—In order to develop pure antiestrogens, a series of 7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman and 7-hydroxy-3-(4-
hydroxyphenyl)-3-methylthiochroman derivatives with sulfoxide containing side chains at the 4-position were designed, synthesized,
and evaluated. Among them, compounds 14b and 24b functioned as pure antiestrogens with the ability to downregulate ER, and
their in vitro and in vivo antiestrogen activities were similar to those of ICI182,780. In addition, the structure–activity relationship
indicated that the (3RS,4RS)-configuration between the 3- and 4-position, the methyl group at the 3-position, the 9-methylene chain
between the scaffold and the sulfoxide moiety, and the terminal perfluoroalkyl moiety play an important role in increasing estrogen
receptor binding and oral antiestrogen activities.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
were expected to eliminate the deleterious effects derived
from the partial agonism in tamoxifen therapy.6,7 In
fact, ICI182,780 demonstrated effectiveness in postmen-
opausal women with advanced breast cancer progres-
sion after tamoxifen therapy in clinical trials,10–12 and
was launched in 2002 as an intramuscular injection drug
for the treatment of hormone receptor positive breast
cancer with disease progression following tamoxifen
therapy (Fig. 1).
Estrogens exert a variety of physiological effects on
reproductive tissue, skeletal, cardiovascular, and central
nervous systems, and compounds which can modulate
signals mediated via estrogen receptors (ER) have been
used for the treatment of breast cancer, osteoporosis,
and hormone replacement therapy.1–3 In particular,
tamoxifen has been widely used for the treatment of hor-
mone-dependent breast cancer for more than two dec-
ades. Tamoxifen is known as an estrogen antagonist;
however, it also has agonist activity, and this partial
agonism has been suggested to cause deleterious effects
such as development of tumor flare, endometrial stimu-
lation, endometrial overgrowth, and endometrial can-
cer.4,5 On the other hand, other antagonists such as
ICI182,780, ICI164,384, and ZM189,154 with no ago-
nist activities were also developed and are known as
pure antiestrogens.6–9 Since these pure antiestrogens
exhibited no agonist activities in preclinical studies, they
Recently, X-ray crystallographic studies disclosed the
binding modes of various ligands with the ER ligand
binding domain (ER-LBD), and estrogen agonists,
SERMs, and pure antiestrogens were found to induce
different conformation changes of helix12 (H12) of ER
in the ligand-ER-LBD complexes. Binding of the endog-
enous estrogen, 17b-estradiol (E2), induced H12 folding
over the surface of ER-LBD, creating a specific coacti-
vator binding site composed of H3, H4, H5, and
H12.13 Coactivator binding to this specific site utilizing
its LXXLL motif is suggested to be essential for an ago-
nist-dependent transcriptional activation. Tamoxifen
and raloxifene, both SERMs, were also found to bind
to ER-LBD and induce H12 folding over the surface
of ER-LBD.13,14 However, the position of the folded
Keywords: Pure antiestrogens; Estrogen; Chroman; Thiochroman.
*
Corresponding author. Tel.: +81 550 87 6727; fax: +81 550 87
5326; e-mail: kanbeyst@chugai-pharm.co.jp
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.03.020

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Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
NMe2
O
N
O
OH
O
O
S
CF2CF3
OH
HO
S
HO
ICI182,780
Raloxifene
Tamoxifen
N
O
O
O
S
OH
F3CF2C
OH
N
HO
HO
MeO
O
ICI164,384
ZM189,154
levormeloxifene
Figure 1. Structure of representative antiestrogens.
H12 was somewhat different from that in the E2-ER-
LBD complex. The amine side chain of tamoxifen or
raloxifene extended toward the outside of ER-LBD,
blocking the H12 folding to the same position as in
the E2-ER-LBD complex. Some parts of H12 seemed
to mimic the LXXLL motif of a coactivator helix, which
induced H12 folding to a coactivator binding site in-
stead. In contrast to E2 and SERMs, pure antiestrogen
ICI164,384 did not induce the H12 folding over ER-
LBD found in the X-ray crystal structure with ER-
LBD.15 The amide side chain of ICI164,384 protruded
from ER-LBD, in which its amide moiety made a hydro-
philic interaction with water and its terminal hydropho-
bic moiety was buried in the AF-2 cleft on the ER-LBD
surface. The AF-2 cleft is considered a key binding site
of H12 when tamoxifen and raloxifene bind to ER-
LBD. These findings suggested that the protruding
amide side chain of ICI164,384 blocked the H12 folding
to the position observed in the E2-ER-LBD complex as
well as to the coactivator binding site observed in the
tamoxifen- and raloxifene-ER-LBD complexes. Regard-
ing the pure antiestrogen ICI182,780, X-ray crystallo-
graphic studies with ER-LBD have not been disclosed
yet. However, we speculate that it would bind to ER-
LBD in a fashion similar to ICI164,384, with its side
chain protruding from ER-LBD, the sulfoxide moiety
creating a hydrophilic interaction with water, and the
terminal hydrophobic moiety buried in the AF-2 cleft.
Based on the structural features of ER-LBD complexed
with different ligands, we assumed that a combination of
a scaffold, which could be accommodated in ER-LBD,
with a side chain, which could take a spatial location
similar to ICI164,384 or ICI182,780, would yield pure
antiestrogens.
In this study, we first investigated whether the
combination of the scaffolds such as 7-hydroxy-3-(4-
hydroxyphenyl)-3-methylthiochroman and 7-hydroxy-
3-(4-hydroxyphenyl)-3-methylchroman with the same
side chain as ICI182,780 would afford pure antiestro-
gens. These scaffolds were selected because of their
similarities to those of pure antiestrogen ZM189,154
and estrogen antagonist levormeloxifene.16 Concerning
the position and configuration of the attached side
chain, 4-position with (3RS,4RS)-configuration was
selected based on the superimposition of these
Figure 2. Superimposition of global minimum conformers of the thiochroman scaffold (green), the chroman scaffold (orange), and the
tetrahydronaphthalene scaffold (light blue) (left). Superimposition of the crystal structure of ICI164,384 (purple) with the global minimum conformer
of the thiochroman scaffold (green) (right). A propyl group was appended to the thiochroman, chroman, and tetrahydronaphthalene scaffold to
clarify the direction of the side chain.

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4805
scaffolds with the tetrahydronaphthalene scaffold in
ZM189,154 and the steroid scaffold in ICI164,384
(Fig. 2). In addition, we also investigated the struc-
ture–activity relationship studies on the relative configu-
ration at the 3,4-position, the methyl group at the 3-
position, the number of methylenes between the scaffold
and the sulfoxide moiety, and the terminal perflu-
oroalkyl moiety.
The chiral isomers of sulfoxide derivative 14b were also
prepared from chiral ketones (R)-6 and (S)-6 using the
same method as in Scheme 2. The chiral resolution of
ketone 6 with a CHIRALCEL OD column afforded chi-
ral ketones (+)-6 and (ꢀ)-6, in which (+)-6 isomer crys-
tallized. X-ray analysis of chiral ketone (+)-6 showed the
absolute configuration to be (R), which consequently
suggested the other to be (S). Both chiral ketones (R)-
6 and (S)-6 were converted to the corresponding
(3S,4S)- and (3R,4R)-sulfoxide derivatives (Scheme 3).
2. Chemistry
The chroman derivatives were prepared from ketone
1618 using a procedure similar to that used for the thi-
ochroman derivatives (Scheme 4). Regarding the chro-
man derivatives, the hydroxyl group at the 4-position
and the alkyne moiety of 1,2-adducts 17a–c were easily
hydrogenated with catalytic hydrogenation, yielding
4-alkyl-substituted derivatives 18a–c. Note that a pro-
longed reaction time gave a mixture of the chroman
derivatives in which the TBS and MOM groups were
deprotected. A relative configuration of chroman deriv-
atives 21a–c and 22a–c was also assigned based on
NOESY 2D NMR spectroscopy and NMR patterns
similar to those used for the thiochroman derivatives.
Sulfoxide derivative 26b bearing no methyl group at
the 3-position was also prepared with a procedure de-
scribed by this laboratory.19
Alkyne derivatives 3a–c were prepared by reaction of
lithium acetylide with TBS-protected bromoalkane
derivatives 2a–c (Scheme 1). The thiochroman deriva-
tives were prepared from ketone 617 according to the
method described in Scheme 2. A nucleophilic 1,2-addi-
tion to ketone 6 with alkyne derivatives 3a–c in the pres-
ence of n-BuLi afforded 1,2-adducts 7a–c. Reduction of
1,2-adducts 7a–c with NaBH3CN in the presence of
ZnI2, and subsequent repetitive catalytic hydrogenation
afforded alcohol derivatives 9a–c as a mixture of
(3RS,4RS)- and (3RS,4SR)-isomers, in which the
(3RS,4RS)-isomer was dominant. Alcohol derivatives
9a–c were converted to corresponding mesylate deriva-
tives 10a–c, and subsequent reaction with 4,4,5,5,5-pen-
tafluoropentyl thioacetate 5a or pentyl thioacetate 5b in
the presence of NaOMe provided (3RS,4RS)-sulfide
derivatives 11a–d and (3RS,4SR)-sulfide derivatives
12a–d, which were separated by column chromatogra-
phy. The relative configuration of each isomer was
determined based on NOESY 2D NMR spectroscopy.
Between sulfide derivatives 11a and 12a, the NOE effect
between the methylene proton at 1-position of the side
chain and the methyl group at the 3-position was
observed in the more polar isomer, but not in the less
polar isomer. Therefore, the more polar isomer was
assigned to be (3RS,4SR)-derivative 12a and the less
polar isomer to be (3RS,4RS)-derivative 11a. As for sul-
fide derivatives 11b–d and 12b–d, a relative configura-
tion was assigned based on the NMR patterns of
(3RS,4RS)-derivative 11a and (3RS,4SR)-derivative
12a. Deprotection of methyl ether of sulfide derivatives
11a–d and 12b with BBr3 yielded corresponding phenol
derivatives 13a–d and 15b. Sulfide derivatives 13a–d
were also converted to corresponding sulfoxide deriva-
tives 14a–d by oxidation with Oxoneꢁ.
3. Results and discussion
The thiochroman and chroman derivatives prepared were
assayed in vitro and in vivo to characterize their profiles
and to investigate their SAR studies. In vitro, a binding
affinity for ERa was determined by displacement of
[3H]estradiol with the test compound utilizing human re-
combinant ERa-LBD. In vivo, estrogen agonist and
antagonist activities were measured by the ability of the
test compound to increase uterine weight gain and to
inhibit estrogen-stimulated uterine weight gain in an
ovariectomized mice model, respectively. Agonist and
antagonist activities were measured to discriminate pure
antiestrogens from SERMs such as tamoxifen and raloxi-
fen. A compound that blocked estrogen-stimulated uter-
ine weight gain as well as exhibiting no significant
uterine weight gain itself was considered a pure
antiestrogen.
Based on the assumption in the introduction, we initially
synthesized thiochroman and chroman derivatives 14b
and 24b which have the same sulfoxide side chain as
ICI182,780 at the 4-position. As shown in Table 1,
compounds 14b and 24b showed considerable affinities
for ERa compared to E2. Subcutaneous administration
of compound 14b and 24b at 300 lg/mouse almost
completely inhibited estrogen-induced uterine weight
gain and showed no significant uterine weight gain when
dosed alone compared to vehicle. Furthermore, oral
administration of compounds 14b and 24b at 10 and
50 mg/kg exhibited antiestrogen activities similar to
those of ICI182,780. We also found compounds 14b
and 24b exhibited ER downregulation effects in MCF-7
cells (unpublished data). These findings indicate that
a
b
Br-(CH2)n-OH
Br-(CH2)n-OTBS
HC C-(CH2)n-OTBS
1a : n = 6
1b : n = 7
1c : n = 8
2a : n = 6
2b : n = 7
2c : n = 8
3a : n = 6
3b : n = 7
3c : n = 8
c, d
R
SAc
R
OH
4a : R = CF2CF3
4b : R = CH2CH3
5a : R = CF2CF3
5b : R = CH2CH3
Scheme 1. Reagents: (a) TBDMSCl, imidazole, MeCN; (b) lithium
acetylide ethylenediamine complex, DMSO, THF; (c) MsCl, Et3N,
CH2Cl2; (d) AcSK, acetone.

4806
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
(CH2)n-OH
(CH2)n-2-OTBS
OMe
(CH2)n-2-OTBS
OMe
OMe
OMe
O
HO
c
b
a
MeO
S
9a : n = 8
9b : n = 9
9c : n = 10
MeO
S
MeO
S
MeO
S
8a : n = 8
8b : n = 9
8c : n = 10
6
7a : n = 8
7b : n = 9
7c : n = 10
(CH2)n-S-(CH2)3R
OMe
(CH2)n-S-(CH2)3R
OMe
(CH2)n-OMs
OMe
e
d
+
MeO
S
MeO
S
MeO
S
10a : n = 8
(3RS,4RS)-isomer
(3RS,4SR)-isomer
12a : n = 8, R = CF2CF3
12b : n = 9, R = CF2CF3
12c : n = 10, R = CF2CF3
12d : n = 9, R = CH2CH3
11a : n = 8, R = CF2CF3
11b : n = 9, R = CF2CF3
11c : n = 10, R = CF2CF3
11d : n = 9, R = CH2CH3
10b : n = 9
10c : n = 10
(CH2)n-S-(CH2)3R
OH
(CH2)n-S-(CH2)3R
OH
(CH2)n-SO-(CH2)3R
OH
f
f
11a-d
g
12b
HO
S
HO
S
(3RS,4SR)-isomer
HO
S
(3RS,4RS)-isomer
(3RS,4RS)-isomer
15b : n = 9, R = CF2CF3
13a : n = 8, R = CF2CF3
13b : n = 9, R = CF2CF3
13c : n = 10, R = CF2CF3
13d : n = 9, R = CH2CH3
14a : n = 8, R = CF2CF3
14b : n = 9, R = CF2CF3
14c : n = 10, R = CF2CF3
14d : n = 9, R = CH2CH3
Scheme 2. Reagents: (a) 3a–c, n-BuLi, THF; (b) ZnI2, NaBH3CN, 1,2-dichloroethane; (c) Pd/C, H2, THF, MeOH; (d) MsCl, Et3N, CH2Cl2; (e) 5a or
5b, NaOMe, MeOH, THF; (f) BBr3, CH2Cl2; (g) oxoneꢁ, THF, H2O.
(CH2)9-SO-(CH2)3CF2CF3
OMe
OH
O
S
a,b,c,d,e,f,g
a,b,c,d,e,f,g
OMe
MeO
HO
S
O
(R)-6
(3S,4S)-14b
chiral separation
MeO
S
(CH2)9-SO-(CH2)3CF2CF3
OH
OMe
O
6
MeO
S
(S)-6
HO
S
(3R,4R)-14b
Scheme 3. Reagents: (a) 3b, n-BuLi, THF; (b) ZnI2, NaBH3CN, 1,2-dichloroethane; (c) Pd/C, H2, THF, MeOH; (d) MsCl, Et3N, CH2Cl2; (e) 5a,
NaOMe, MeOH, THF; (f) BBr3, CH2Cl2; (g) oxoneꢁ, THF, H2O.
compounds 14b and 24b functioned as pure antiestrogens
with the ability to downregulate ER, and their oral anti-
estrogen activities were similar to those of ICI182,780.
and similar antiestrogen activities when dosed subcuta-
neously and orally. It is interesting to note that
although the directions of both the side chains are com-
pletely opposite when the hydroxyl groups at the 7-po-
sition and the 40-position of one isomer are overlaid on
the respective hydroxyl groups at the 7-position and the
40-position of the other, their binding affinities for ERa
were almost the same. Flipping one scaffold 180ꢂ about
its longest (hydroxy-to-hydroxy) axis and rotating it
so that the hydroxyl group at the 7-position superim-
Having confirmed that the thiochroman and chroman
scaffolds with the same side chain as ICI182,780 yielded
pure antiestrogens 14b and 24b, chiral isomers of 14b
were then synthesized and evaluated. As shown in Table
2, both the chiral isomers of 14b, (3R,4R)-14b and
(3S,4S)-14b, showed same binding affinities for ERa

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4807
(CH2)n-2-OTBS
(CH2)n-OTBS
(CH2)n-OH
OMOM
OMOM
OMOM
OMOM
O
HO
c
b
a
MOMO
O
19a : n = 8
19b : n = 9
19c : n = 10
MOMO
O
MOMO
O
MOMO
O
18a : n = 8
18b : n = 9
18c : n = 10
16
17a : n = 8
17b : n = 9
17c : n = 10
(CH2)n-S-(CH2)3CF2CF3
OMOM
(CH2)n-S-(CH2)3CF2CF3
OMOM
(CH2)n-OMs
OMOM
e
d
+
MOMO
O
MOMO
O
MOMO
O
(3RS,4RS)-isomer
21a : n = 8
21b : n = 9
(3RS,4SR)-isomer
20a : n = 8
20b : n = 9
20c : n = 10
22a : n = 8
22b : n = 9
22c : n = 10
21c : n = 10
(CH2)n-SO2-(CH2)3CF2CF3
OH
(CH2)n-SO-(CH2)3CF2CF3
OH
(CH2)n-S-(CH2)3CF2CF3
OH
f
g
h
21a-c
23b
HO
O
HO
O
HO
O
(3RS,4RS)-isomer
25b : n = 9
(3RS,4RS)-isomer
(3RS,4RS)-isomer
23a : n = 8
23b : n = 9
23c : n = 10
24a : n = 8
24b : n = 9
24c : n = 10
Scheme 4. Reagents: (a) 3a–c, n-BuLi, THF; (b) Pd/C, H2, AcOEt; (c) PPTS, CH2Cl2, MeOH; (d) MsCl, Et3N, CH2Cl2; (e) 5a, NaOMe, MeOH,
THF; (f) HCl–MeOH; (g) oxoneꢁ (0.6 equiv), THF, H2O; (h) oxoneꢁ (3 equiv), THF, H2O.
Table 1. Biological data of compounds 14b and 24b
(CH2)3 CF2CF3
OS
(CH2)9
OH
Me
HO
X
Compound
X
RBAa (%) E2 = 100
Antiestrogen activityb
(% inhibition)
Estrogen activityc
(% uterine weight gain)
30 lg/mouse (sc) 300 lg/mouse (sc) 10 mg/kg (po) 50 mg/kg (po) 300 lg/mouse (sc)
14b
24b
S
200
96
83
90
79
75
101
94
51
66
42
54
94
88
76
86
ꢀ2*
O
1*
ZM189,154 CH2 169
ICI182,780 138
97
95
4*
ꢀ1*
a Relative binding affinities for the recombinant estrogen receptor (ERa), determined by competitive radiometric binding assay with [3H]estradiol.
b Inhibition of estradiol-stimulated uterine weight gain by the test compound with subcutaneous (sc) or oral (po) administration.
c Stimulation of uterine weight gain by the test compound with sc administration.
* No significant difference between the test group and the vehicle group at P < 0.05 using Student’s t test.
Table 2. Biological data of compounds (3R,4R)-14b and (3S,4S)-14b
Compound
RBAa (%) E2 = 100
Antiestrogen activityb (% inhibition)
3 lg/mouse (sc)
30 lg/mouse (sc)
25 mg/kg (po)
(3R,4R)-14b
(3S,4S)-14b
200
200
22
13
87
71
47
37
14b
200
n.t.
83
51 (10 mg/kg)
n.t., not tested.
a Relative binding affinities for the recombinant estrogen receptor (ERa), determined by competitive radiometric binding assay with [3H]estradiol.
b Inhibition of estradiol-stimulated uterine weight gain by the test compound with sc or po administration.

4808
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
poses on the hydroxyl group at the 40-position of the
other isomer lead to both side chains extending almost
the same axial direction and both scaffolds occupying
a similar space (Fig. 3). We speculated that these con-
formers would equally contribute to the binding affin-
ity for ERa and they did indeed show almost the
same affinity for ERa.
yl group at the 3-position, the number of methylenes be-
tween the scaffold and the sulfoxide moiety, the terminal
perfluoro moiety, and the oxidation state of the sulfur
atom at the side chain (Table 3). With respect to the rel-
ative configuration between the 3- and 4-position,
(3RS,4RS)-isomer 13b showed higher binding affinity
than corresponding (3RS,4SR)-isomer 15b. Conforma-
tion analysis showed that the directions of the side
chains of both isomers were quite different: almost axial
in (3RS,4RS)-isomer 13b and almost equatorial in
(3RS,4SR)-isomer 15b. Axial directed side chains were
also observed at the 7-position of pure antiestrogens
ICI164,384 and ICI182,780. This information, togeth-
er with our data, suggested that (3RS,4RS)-configura-
tion, its side chain being almost axial, was important
for high affinity for ERa and potent antiestrogen
activities.
We next turned our attention to the SAR studies on the
relative configuration at the 3- and 4-position, the meth-
Replacement of the methyl group at the 3-position with a
hydrogen atom decreased the binding affinity for ERa as
well as antiestrogen activities with oral administration
(24b vs 26b). Perhaps, this is because the methyl group
at the 3-position would lead the 3-aryl group to take a
location almost identical to the chroman ring, in which
the whole conformation would function as an alternative
to the steroid scaffold and more potent activities would be
observed.
Figure 3. Superimposition of the global minimum conformers of
(3R,4R)- and (3S,4S)-thiochroman derivatives (magenta and green,
respectively). A propyl group was appended to the thiochroman and
chroman scaffolds to simplify and clarify the scaffold and the direction
of the side chains.
Table 3. Biological data of thiochroman and chroman derivatives
(CH2)3 R1
L
(CH2)n
OH
R2
HO
X
Compound
n
X
R1
R2
L
RBAa (%) E2 = 100
Antiestrogen activityb (%inhibition)
30 lg/mouse (sc)
10 mg/kg (po)
50 mg/kg (po)
14a
13b
15bc
14b
14d
14c
8
9
9
9
9
S
S
S
S
S
S
CF2CF3
CF2CF3
CF2CF3
CF2CF3
CH2CH3
CF2CF3
Me
Me
Me
Me
Me
Me
SO
S
230
59
90
21
2
43
n.t.
n.t.
51
0
77
n.t.
n.t.
94
S
7
SO
SO
SO
200
120
220
83
84
56
20
78
10
29
24a
23b
24b
26b
25b
24c
8
9
O
O
O
O
O
O
CF2CF3
CF2CF3
CF2CF3
CF2CF3
CF2CF3
CF2CF3
Me
Me
Me
H
SO
S
150
29
67
19
90
0
33
32
66
13
37
54
58d
78d
81d
46
63d
79d
9
SO
SO
SO2
SO
96
37
9
9
10
Me
Me
130
100
88
81
ICI182,780
138
75
54
86
n.t., not tested.
a Relative binding affinities for the recombinant estrogen receptor (ERa), determined by competitive radiometric binding assay with [3H]estradiol.
b Inhibition of estradiol-stimulated uterine weight gain by the test compound with sc or po administration.
c Relative configuration is (3RS,4SR).
d 30 mg/kg, po.

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4809
As far as the number of methylenes between the scaffold
and the sulfoxide moiety is concerned, thiochroman and
chroman derivatives with the 8-, 9-, and 10-methylenes,
14a–c and 24a–c, demonstrated similar and considerable
binding affinities for ERa compared to ICI182,780.
These side chains are so flexible that the sulfoxide and
terminal perfluoro moieties can take similar locations
to ICI182,780, which would attribute to the similar
and considerable binding affinities for ERa. Further-
more, compounds 14a–c and 24a–c showed potent anti-
estrogen activities with oral administration, of which
compounds bearing 9-methylenes, 14b and 24b, were
most potent.
tetramethylsilane as an internal standard or by refer-
ence to proton resonances resulting from incomplete
deuteration of NMR solvent. All coupling constants
were described in Hertz (Hz). High-resolution mass
spectra (HRMS) were performed on a Micromass Q-
TOF Ultima spectrometer, and low-resolution mass
spectra (LRMS) were performed on a Thermo Elec-
tron LCQ-Classic spectrometer or a Waters ZQ2000
spectrometer.
5.1. 1-Bromo-6-(tert-butyldimethylsilyloxy)hexane (2a)
A
mixture of 6-bromohexan-1-ol (1a) (4.84 g,
26.7 mmol), imidazole (2.79 g, 41.0 mmol), and tert-
butyldimethylchlorosilane (6.18 g, 41.0 mmol) in aceto-
nitrile (50 mL) was stirred at room temperature for 24
h. The precipitate was filtered off, and the residue was
concentrated and purified with column chromatography
(n-hexane/ethyl acetate = 40:1) to afford 4.25 g (54%) of
2a. 1H NMR (270 MHz, CDC13): d 3.61 (2H, t,
J = 6.3 Hz), 3.41 (2H, t, J = 6.8 Hz), 1.92–1.81 (2H,
m), 1.56–1.30 (6H, m), 0.89 (9H, s), 0.05 (6H, s).
It is noteworthy to mention that although compounds
14b and 14d showed high binding affinities for ERa
and similar antiestrogen activities with subcutaneous
administration, oral administration at 10 and 50 mg/kg
afforded quite different antiestrogen activities. The struc-
tural difference between these compounds was the termi-
nal alkyl moiety of the side chain. We speculated that
the terminal alkyl moiety would be easily metabolized
by x and x-1 oxidation, whereas the terminal perflu-
oroalkyl moiety would block this oxidation, attributing
to the quite different oral antiestrogen activities between
these compounds. The effect of the terminal perflu-
oroalkyl moiety inhibiting x and x-1 oxidation has been
mentioned in a previous study.20
5.2. 1-Bromo-7-(tert-butyldimethylsilyloxy)heptane (2b)
This compound was prepared from 1b using a procedure
similar to that described for 2a. H NMR (400 MHz,
1
CDC13): d 3.60 (2H, t, J = 6.4 Hz), 3.40 (2H, t,
J = 7.0 Hz), 1.87–1.84 (2H, m), 1.51–1.33 (8H, m), 0.89
(9H, s), 0.04 (6H, s).
The compounds having the sulfoxide or the sulfone moi-
ety in the side chain, 24b and 25b, showed more potent
receptor binding affinities than one having the sulfide
moiety, 23b. As previously mentioned, we speculated
that the binding mode of these compounds would be
similar to ICI164,384, and therefore, the compounds
having a more hydrophilic moiety such as the sulfoxide
or the sulfone moiety would create a stronger hydrophil-
ic interaction with water and show higher affinities for
ER.
5.3. 1-Bromo-8-(tert-butyldimethylsilyloxy)octane (2c)
This compound was prepared from 1c using a procedure
similar to that described for 2a. H NMR (270 MHz,
1
CDC13): d 3.59 (2H, t, J = 6.3 Hz), 3.39 (2H, t,
J = 6.8 Hz), 1.88–1.77 (2H, m), 1.60–1.20 (10H, m),
0.89 (9H, s), 0.04 (6H, s).
5.4. 8-(tert-Butyldimethylsilyloxy)-oct-1-yne (3a)
4. Conclusion
To a stirred mixture of lithium acetylide ethylenedia-
mine complex (90%, 2.82 g, 27.6 mmol) in dimethylsulf-
oxide (17 mL) and tetrahydrofuran (7 mL) was added a
tetrahydrofuran solution (7 mL) of 2a (4.07 g,
13.8 mmol) at ꢀ10 ꢂC, and the reaction mixture was al-
lowed to warm to room temperature overnight. The
reaction mixture was poured into water and extracted
with ether. The extract was dried over anhydrous mag-
nesium sulfate and concentrated. The crude product
was purified with column chromatography (n-hexane/
In summary, we found that compounds 14b and 24b
functioned as pure antiestrogens with the ability to
downregulate ER, and their in vitro and in vivo anties-
trogen activities were similar to those of ICI182,780. In
addition, SAR studies indicated that (3RS,4RS)-config-
uration between the 3- and 4-position, the methyl group
at the 3-position, the 9-methylene chain between the
scaffold and the sulfoxide moiety, a more polar moiety
such as the sulfoxide or the sulfone in the side chain,
and the terminal perfluoroalkyl moiety play an impor-
tant role in increasing ERa binding affinities and oral
antiestrogen activities.
1
ethyl acetate = 50:1) to afford 1.76 g (53%) of 3a. H
NMR (270 MHz, CDC13): d 3.60 (2H, t, J = 6.5 Hz),
2.21–2.15 (2H, m), 1.93 (1H, t, J = 2.6 Hz), 1.59–1.37
(8H, m), 0.89 (9H, s), 0.05 (6H, s).
5.5. 9-(tert-Butyldimethylsilyloxy)-non-1-yne (3b)
5. Experimental
This compound was prepared from 2b using a procedure
similar to that described for 3a. H NMR (270 MHz,
CDC13): d 3.59 (2H, t, J = 6.5 Hz), 2.21–2.13 (2H, m),
1.92 (1H, t, J = 2.6 Hz), 1.52–1.23 (10H, m), 0.88 (9H,
s), 0.04 (6H, s).
1
Proton nuclear magnetic resonance (1H NMR) spectra
were recorded on a JEOL JNM-ECP400 (400 MHz) or
a JEOL JNM-EX270 (270 MHz) spectrometer. Chemi-
cal shifts were reported in parts per million (ppm) with

4810
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
5.6. 10-(tert-Butyldimethylsilyloxy)-dec-1-yne (3c)
5.10. 4-[8-(tert-Butyldimethylsilyloxy)-oct-1-ynyl]-7-
methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-ol
(7a)
This compound was prepared from 2c using a procedure
similar to that described for 3a. H NMR (270 MHz,
1
CDC13): d 3.59 (2H, t, J = 6.5 Hz), 2.21–2.13 (2H, m),
1.92 (1H, t, J = 2.7 Hz), 1.64–1.30 (12H, m), 0.89 (9H,
s), 0.04 (6H, s).
This compound was prepared from 6 and 3a using a
procedure similar to that described for 7b. H NMR
1
(400 MHz, CDCl3) d: 7.85 (1H, d, J = 8.4 Hz, ArH),
7.60 (2H, d, J = 8.4 Hz, ArH), 6.88 (2H, d, J = 8.4 Hz,
ArH), 6.67–6.63 (2H, m, ArH), 4.26 (1H, d,
J = 12.3 Hz, H-2), 3.81 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 3.60 (2H, t, J = 6.4 Hz, CH2OTBS), 2.71 (1H,
d, J = 12.3 Hz, H-2), 2.20–2.17 (3H, m, OH and
CꢁCCH2), 1.62–1.24 (11H, m, C3-CH3 and
(CH2)4CH2OTBS), 0.89 (9H, s, TBS), 0.05 (6H, s, TBS).
5.7. 4,4,5,5,5-Pentafluoropentyl thioacetate (5a)
To a dichloromethane solution (200 mL) of 4,4,5,5,5-
pentafluoropentanol (23.2 g, 130 mmol) and triethyl-
amine (27.0 g, 267 mmol) was added methanesulfonyl
chloride (30.0 g, 262 mmol) at 0 ꢂC, and the reaction
mixture was allowed to warm to room temperature over-
night. The reaction mixture was poured into water and
extracted with chloroform. The extract was dried over
anhydrous magnesium sulfate and concentrated to give
33.9 g of 4,4,5,5,5-pentafluoropentyl methanesulfonate.
Then, to an acetone solution (500 mL) of the obtained
4,4,5,5,5-pentafluoropentyl methanesulfonate (33.9 g)
was added potassium thioacetate (18.0 g, 158 mmol)
and stirred at room temperature for 12 h. The precipitate
was filtered off and the residue was concentrated. The
crude product was purified with column chromatogra-
phy (n-hexane/ethyl acetate = 20:1) to afford 15.8 g
5.11. 4-[10-(tert-Butyldimethylsilyloxy)-dec-1-ynyl]-7-
methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-ol
(7c)
This compound was prepared from 6 and 3c using a pro-
cedure similar to that described for 7b. 1H NMR
(400 MHz, CDCl3) d: 7.86 (1H, d, J = 8.8 Hz, ArH),
7.60 (2H, d, J = 8.4 Hz, ArH), 6.88 (2H, d, J = 8.4 Hz,
ArH), 6.67–6.63 (2H, m, ArH), 4.26 (1H, d,
J = 12.4 Hz, H-2), 3.81 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 3.59 (2H, t, J = 6.4 Hz, CH2OTBS), 2.70 (1H,
d, J = 12.4 Hz, H-2), 2.19–2.16 (3H, m, OH and
CꢁCCH2), 1.62–1.24 (15H, m, C3-CH3 and
(CH2)6CH2OTBS), 0.89 (9H, s, TBS), 0.05 (6H, s, TBS).
1
(51%) of 5a. H NMR (270 MHz, CDC13): d 2.95 (2H,
t, J = 6.9 Hz), 2.35 (3H, s), 2.20–1.83 (4H, m).
5.8. Pentyl thioacetate (5b)
5.12. 9-[7-Methoxy-3-(4-methoxyphenyl)-3-methylthio-
chroman-4-yl]-nonan-1-ol (9b)
This compound was prepared from 4b using a procedure
similar to that described for 5a. H NMR (270 MHz,
1
A mixture of 7b (1.64 g, 2.88 mmol), zinc iodide (1.30 g,
4.07 mmol), and sodium cyanoborohydride (1.30 g,
20.7 mmol) in 1,2-dichloroethane (40 mL) was stirred
for 2 h at room temperature. Then, the reaction mixture
was poured into water and extracted with ethyl acetate.
The extract was dried over anhydrous magnesium sul-
fate, concentrated, and purified with column chroma-
tography (n-hexane/ethyl acetate = 10:1 ! 5:1) to
afford 0.78 g (52%) of crude 8b. Then a mixture of 8b
(0.78 g, 1.4 mmol) and 10% Pd/C (0.27 g) in methanol
(40 mL) and tetrahydrofuran (5 mL) was stirred at room
temperature for 12 h under hydrogen atmosphere. The
reaction mixture was filtered to remove 10% Pd/C and
concentrated. Again, methanol (30 mL), tetrahydrofu-
ran (5 mL), and 10% Pd/C (0.27 g) were added to this
residue, and the mixture was stirred for 12 h under
hydrogen atmosphere. Then, the reaction mixture was
filtered to remove 10% Pd/C and concentrated. Further-
more, methanol (30 mL), tetrahydrofuran (5 mL), and
10% Pd/C (0.25 g) were added to this residue, and the
mixture was stirred for 12 h under hydrogen atmo-
sphere. Then, the reaction mixture was filtered to re-
move 10% Pd/C and concentrated. The crude product
was purified with column chromatography (n-hexane/
ethyl acetate = 10:1 ! 2:1) to afford 0.35 g (56% from
8b, 3RS,4RS/3RS,4SR = 7:l) of 9b. 1H NMR
(270 MHz, CDCl3) d: 7.29 (2H, d, J = 8.9 Hz, ArH of
cis- and trans-isomer), 6.94–6.42 (5H, m, ArH of cis-
and trans-isomer), 3.82–3.60 (8H + 7/8H, m, OCH3
and CH2OH of cis- and trans-isomer, and H-2 of cis-
CDC13): d 2.86 (2H, t, J = 7.3 Hz), 2.31 (3H, s), 1.60–
1.51 (2H, m), 1.36–1.30 (4H, m), 0.89 (3H, t,
J = 6.8 Hz).
5.9. 4-[9-(tert-Butyldimethylsilyloxy)-non-1-ynyl]-7-
methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-ol
(7b)
To a tetrahydrofuran solution (10 mL) of 3b (1.66 g,
6.52 mmol) was added a 2.70 M n-hexane solution of
n-butyl lithium (2.20 mL, 5.94 mmol) at ꢀ20 ꢂC under
N2 atmosphere, and the reaction mixture was stirred
for 1 h at ꢀ20 ꢂC. Then a tetrahydrofuran solution
(10 mL) of 6 (923 mg, 2.94 mmol) was added to the
reaction mixture and stirred for 2 h at ꢀ10 ꢂC. The
reaction mixture was poured into water and extracted
with ethyl acetate. The extract was dried over anhy-
drous magnesium sulfate, concentrated, and purified
with column chromatography (n-hexane/ethyl ace-
tate = 10:1 ! 5:1) to afford 1.64 g (98%) of 7b. 1H
NMR (400 MHz, CDCl3) d: 7.86 (1H, d, J = 8.8 Hz,
ArH), 7.60 (2H, d, J = 8.1 Hz, ArH), 6.88 (2H, d,
J = 8.1 Hz, ArH), 6.67–6.63 (2H, m, ArH), 4.26 (1H,
d, J = 12.3 Hz, H-2), 3.81 (3H, s, OCH3), 3.78 (3H,
s, OCH3), 3.60 (2H, t, J = 6.4 Hz, CH2OTBS), 2.71
(1H, d, J = 12.3 Hz, H-2), 2.20–2.18 (3H, m, OH and
CꢁCCH2), 1.59–1.26 (13H, m, C3-CH3 and
(CH2)5CH2OTBS), 0.89 (9H, s, TBS), 0.05 (6H, s,
TBS).

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4811
isomer), 3.24 (2/8H, s, H-2 of trans-isomer), 2.99 (7/8H,
5.16. 8-[7-Methoxy-3-(4-methoxyphenyl)-3-methylthio-
chroman-4-yl]-octyl methanesulfonate (10a)
d, J = 11.5 Hz, H-2 of cis-isomer), 2.92 (1/8H, br s, H-4
of trans-isomer), 2.74 (7/8H, br s, H-4 of cis-isomer),
1.59–1.08 (19H, m, (CH2)8CH2OH and C3-CH3 of cis-
and trans-isomer).
This compound (3RS,4RS/3RS,4SR = 5:l) was prepared
from 9a (3RS,4RS/3RS,4SR = 5:l) using a procedure
similar to that described for 10b. H NMR (400 MHz,
1
CDCl3) d: 7.30 (2H, d, J = 7.7 Hz, ArH of cis- and
trans-isomer), 6.93–6.40 (5H, m, ArH of cis- and trans-
isomer), 4.17 (2H, t, J = 6.6 Hz, CH2OMs of cis- and
trans-isomer), 3.83 (15/6H, s, OCH3 of cis-isomer),
3.78 (15/6H, s, OCH3 of cis-isomer), 3.71 (3/6H, s,
OCH3 of trans-isomer), 3.66 (3/6H, s, OCH3 of trans-
isomer), 3.65 (5/6H, d, J = 12.5 Hz, H-2 of cis-isomer),
3.24 (2/6H, br s, H-2 of trans-isomer), 3.00–2.98
(3H + 5/6H, m, OMs of cis- and trans-isomer, and H-2
of cis-isomer), 2.91 (1/6H, br s, H-4 of trans-isomer),
2.73 (5/6H, br s, H-4 of cis-isomer), 1.75–1.01 (17H,
m, (CH2)7CH2OMs and C3-CH3 of cis- and trans-
isomer).
5.13. 8-[7-Methoxy-3-(4-methoxyphenyl)-3-methylthio-
chroman-4-yl]-octan-1-ol (9a)
This compound (3RS,4RS/3RS,4SR = 5:l) was prepared
from 7a using a procedure similar to that described for
9b. 1H NMR (400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.1 Hz, ArH of cis- and trans-isomer), 6.94–6.40
(5H, m, ArH of cis- and trans-isomer), 3.83–3.56
(8H + 5/6H, m, OCH3 and CH2OH of cis- and trans-iso-
mer, and H-2 of cis-isomer), 3.24 (2/6H, s, H-2 of trans-
isomer), 2.99 (5/6H, d, J = 11.7 Hz, H-2 of cis-isomer),
2.91 (1/6H, br s, H-4 of trans-isomer), 2.73 (5/6H, br s,
H-4 of cis-isomer), 1.59–1.08 (17H, m, (CH2)7CH2OH
and C3-CH3 of cis- and trans-isomer).
5.17. 10-[7-Methoxy-3-(4-methoxyphenyl)-3-methylthi-
ochroman-4-yl]-decyl methanesulfonate (10c)
5.14. 10-[7-Methoxy-3-(4-methoxyphenyl)-3-methyl-
thiochroman-4-yl]-decan-1-ol (9c)
This compound (3RS,4RS/3RS,4SR = 7:l) was prepared
from 9c (3RS,4RS/3RS,4SR = 7:l) using a procedure
similar to that described for 10b. H NMR (400 MHz,
This compound (3RS,4RS/3RS,4SR = 7:l) was prepared
from 7c using a procedure similar to that described for
9b. 1H NMR (400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.1 Hz, ArH of cis- and trans-isomer), 6.94–6.39
(5H, m, ArH of cis- and trans-isomer), 3.82–3.59
(8H + 7/8H, m, OCH3 and CH2OH of cis- and trans-iso-
mer, and H-2 of cis-isomer), 3.24 (2/8H, s, H-2 of trans-
isomer), 2.99 (7/8H, d, J = 11.4 Hz, H-2 of cis-isomer),
2.91 (1/8H, br s, H-4 of trans-isomer), 2.73 (7/8H, br s,
H-4 of cis-isomer), 1.61–1.08 (21H, m, (CH2)9CH2OH
and C3-CH3 of cis- and trans-isomer).
1
CDCl3) d: 7.29 (2H, d, J = 8.1 Hz, ArH of cis- and
trans-isomer), 6.94–6.41 (5H, m, ArH of cis- and trans-
isomer), 4.20 (2H, t, J = 6.6 Hz, CH2OMs of cis- and
trans-isomer), 3.82 (21/8H, s, OCH3 of cis-isomer),
3.78 (21/8H, s, OCH3 of cis-isomer), 3.71 (3/8H, s,
OCH3 of trans-isomer), 3.66 (3/8H, s, OCH3 of trans-
isomer), 3.65 (7/8H, d, J = 12.5 Hz, H-2 of cis-isomer),
3.24 (2/8H, s, H-2 of trans-isomer), 2.99–2.97 (3H + 7/
8H, m, OMs of cis- and trans-isomer, and H-2 of cis-iso-
mer), 2.92 (1/8H, br s, H-4 of trans-isomer), 2.73 (7/8H,
br s, H-4 of cis-isomer), 1.73–1.10 (21H, m,
(CH2)9CH2OMs and C3-CH3 of cis- and trans-isomer).
5.15. 9-[7-Methoxy-3-(4-methoxyphenyl)-3-methylthio-
chroman-4-yl]nonyl methanesulfonate (10b)
5.18. (3RS,4RS)-7-Methoxy-3-(4-methoxyphenyl)-3-
methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)-
nonyl]thiochroman (11b) and (3RS,4SR)-7-Methoxy-3-
(4-methoxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-penta-
fluoropentylsulfanyl)nonyl]thiochroman (12b)
A
mixture of 9b (0.35 g, 0.79 mmol, 3RS,4RS/
3RS,4SR = 7:l), methanesulfonyl chloride (0.27 g,
2.36 mmol), and triethylamine (0.24 g, 2.38 mmol) in
dichloromethane (10 mL) was stirred at room temper-
ature for 2 h. The reaction mixture was poured into
water and extracted with dichloromethane. The extract
was dried over anhydrous magnesium sulfate, concen-
trated, and purified with column chromatography (n-
hexane/ethyl acetate = 10:1 ! 3:1) to afford 0.41 g
(quant.) of 10b (3RS,4RS/3RS,4SR = 7:l). 1H NMR
(400 MHz, CDCl3) d: 7.29–7.24 (2H, m, ArH of cis-
and trans-isomer), 6.93–6.40 (5H, m, ArH of cis-
and trans-isomer), 4.17 (2H, t, J = 6.6 Hz, CH2OMs
of cis- and trans-isomer), 3.81 (21/8H, s, OCH3 of
cis-isomer), 3.76 (21/8H, s, OCH3 of cis-isomer), 3.69
(3/8H, s, OCH3 of trans-isomer), 3.65 (3/8H, s,
OCH3 of trans-isomer), 3.63 (7/8H, d, J = 10.2 Hz,
H-2 of cis-isomer), 3.23 (2/8H, s, H-2 of trans-isomer),
2.98–2.95 (3H + 7/8H, m, OMs of cis- and trans-iso-
mer, and H-2 of cis-isomer), 2.90 (1/8H, br s, H-4
of trans-isomer), 2.73 (7/8H, br s, H-4 of cis-isomer),
1.70–1.07 (19H, m, (CH2)8CH2OMs and C3-CH3 of
cis- and trans-isomer).
To a stirred solution of 5a (571 mg, 2.42 mmol) in meth-
anol (3 mL) was added a 1.0 M methanol solution of
sodium methoxide (2.18 mL, 2.18 mmol) and stirred
for 1 h at room temperature. Then, 10b (210 mg,
0.40 mmol, 3RS,4RS/3RS,4SR = 7:l) in tetrahydrofuran
(3 mL) was added to this reaction mixture and stirred
for 12 h at room temperature. The reaction mixture
was neutralized with 50% acetic acid, poured into water,
and extracted with ethyl acetate. The extract was washed
with water, dried over anhydrous magnesium sulfate,
and concentrated. The crude product was purified with
chromatography (n-hexane/ethyl acetate = 50:1 ! 20:1)
to afford 197 mg (79%) of 11b and 28 mg (11%) of 12b.
1H NMR (11b, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.4 Hz, ArH), 6.94–6.89 (3H, m, ArH), 6.73 (1H,
s, ArH), 6.58 (1H, d, J = 8.4 Hz, ArH), 3.82 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.64 (1H, d, J = 11.4 Hz,

4812
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
H-2), 2.99 (1H, d, J = 11.4 Hz, H-2), 2.73 (1H, br s, H-
4), 2.57 (2H, t, J = 7.0 Hz, CH2S), 2.47 (2H, t,
H-4), 2.58 (2H, t, J = 7.0 Hz, CH2S), 2.48 (2H, t,
J = 7.3 Hz, CH2S), 2.23–2.10 (2H, m,
J = 7.3 Hz,
CH2S),
2.23–2.10
(2H,
m,
CH2CH2CF2CF3), 1.91–1.84 (2H, m, CH2CH2CF2CF3),
1.58–1.10 (21H, m, (CH2)9CH2S and C3-CH3); MS
(m/z) 633 (M+1).
CH2CH2CF2CF3), 1.91–1.83 (2H, m, CH2CH2CF2CF3),
1.55–1.08 (19H, m, (CH2)8CH2S and C3-CH3); MS
(m/z) 619 (M+1).
1H NMR (12c, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.1 Hz, ArH), 6.75–6.69 (3H, m, ArH), 6.53 (1H,
s, ArH), 6.40 (1H, d, J = 8.1 Hz, ArH), 3.71 (3H, s,
OCH3), 3.66 (3H, s, OCH3), 3.24 (2H, s, H-2), 2.91
(1H, br s, H-4), 2.59 (2H, t, J = 7.0 Hz, CH2S), 2.50
(2H, t, J = 7.3 Hz, CH2S), 2.22–2.10 (2H, m,
CH2CH2CF2CF3), 1.92–1.86 (2H, m, CH2CH2CF2CF3),
1.66–1.24 (21H, m, (CH2)9CH2S and C3-CH3); MS
(m/z) 633 (M+1).
1H NMR (12b, 400 MHz, CDCl3) d: 7.30 (2H, d,
J = 8.1 Hz, ArH), 6.74 (1H, d, J = 8.2 Hz, ArH), 6.70
(2H, d, J = 8.1 Hz, ArH), 6.53 (1H, s, ArH), 6.40 (1H,
d, J = 8.2 Hz, ArH), 3.71 (3H, s, OCH3), 3.66 (3H, s,
OCH3), 3.24 (2H, s, H-2), 2.91 (1H, br s, H-4), 2.59
(2H, t, J = 7.0 Hz, CH2S), 2.50 (2H, t, J = 7.3 Hz,
CH2S), 2.24–2.10 (2H, m, CH2CH2CF2CF3), 1.92–1.84
(2H, m, CH2CH2CF2CF3), 1.67–1.25 (19H, m,
(CH2)8CH2S and C3-CH3).
5.21. (3RS,4RS)-7-Methoxy-3-(4-methoxyphenyl)-3-
methyl-4-[9-(pentylsulfanyl)nonyl]thiochroman (11d) and
(3RS,4SR)-7-Methoxy-3-(4-methoxyphenyl)-3-methyl-4-
[9-(pentylsulfanyl)nonyl]thiochroman (12d)
5.19. (3RS,4RS)-7-Methoxy-3-(4-methoxyphenyl)-3-
methyl-4-[8-(4,4,5,5,5-pentafluoropentylsulfanyl)octyl]
thiochroman (11a) and (3RS,4SR)-7-Methoxy-3-(4-
methoxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-penta-
fluoropentylsulfanyl)octyl]thiochroman (12a)
These compounds, 11d (79%) and 12d (10%), were pre-
pared from 10b (3RS,4RS/3RS,4SR = 7:l) and 5b using
a procedure similar to that described for 11b and 12b.
These compounds, 11a (76%) and 12a (16%), were pre-
pared from 10a (3RS,4RS/3RS,4SR = 5:l) and 5a using
a procedure similar to that described for 11b and 12b.
1H NMR (11d, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.4 Hz, ArH), 6.93–6.89 (3H, m, ArH), 6.73 (1H,
s, ArH), 6.58 (1H, d, J = 8.4 Hz, ArH), 3.82 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.64 (1H, d, J = 11.4 Hz,
H-2), 2.99 (1H, d, J = 11.4 Hz, H-2), 2.73 (1H, br s,
H-4), 2.50–2.45 (4H, m, CH2S CH2), 1.56–0.88 (28H,
m, (CH2)8CH2SCH2(CH 2)3CH3 and C3-CH3); MS
(m/z) 529 (M+1).
1H NMR (11a, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.4 Hz, ArH), 6.93–6.89 (3H, m, ArH), 6.73 (1H,
s, ArH), 6.58 (1H, d, J = 8.4 Hz, ArH), 3.82 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.64 (1H, d, J = 11.6 Hz,
H-2), 2.99 (1H, d, J = 11.6 Hz, H-2), 2.73 (1H, br s,
H-4), 2.57 (2H, t, J = 7.0 Hz, CH2S), 2.45 (2H, t,
J = 7.3 Hz,
CH2S),
2.22–2.09
(2H,
m,
CH2CH2CF2CF3), 1.90–1.83 (2H, m, CH2CH2CF2CF3),
1.56–1.01 (17H, m, (CH2)7CH2S and C3-CH3); MS
(m/z) 605 (M+1).
1H NMR (12d, 400 MHz, CDCl3) d: 7.30 (2H, d,
J = 8.8 Hz, ArH), 6.74 (1H, d, J = 8.4 Hz, ArH), 6.70
(2H, d, J = 8.8 Hz, ArH), 6.53 (1H, d, J = 2.6 Hz,
ArH), 6.40 (1H, dd, J = 8.4, 2.6 Hz, ArH), 3.71 (3H, s,
OCH3), 3.66 (3H, s, OCH3), 3.24 (2H, s, H-2), 2.91
(1H, br s, H-4), 2.51–2.48 (4H, m, CH2SCH2), 1.57–
0.88 (28H, m, (CH2)8CH2SCH2(CH 2)3CH3 and C3-
CH3).
1H NMR (12a, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.4 Hz, ArH), 6.74 (1H, d, J = 8.4 Hz, ArH), 6.70
(2H, d, J = 8.4 Hz, ArH), 6.53 (1H, s, ArH), 6.40 (1H,
d, J = 8.4 Hz, ArH), 3.71 (3H, s, OCH3), 3.66 (3H, s,
OCH3), 3.24 (2H, s, H-2), 2.91 (1H, br s, H-4), 2.58
(2H, t, J = 7.0 Hz, CH2S), 2.49 (2H, t, J = 7.3 Hz,
CH2S), 2.23–2.10 (2H, m, CH2CH2CF2CF3), 1.92–1.84
(2H, m, CH2CH2CF2CF3), 1.66–1.25 (17H, m,
(CH2)7CH2S and C3-CH3); MS (m/z) 605 (M+1).
5.22. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]thio-
chroman-7-ol (13b)
To a stirred solution of 11b (120 mg 0.19 mmol) in
dichloromethane (8 mL) was added a 1.0 M dichloro-
methane solution of boron tribromide (2.0 mL,
2.0 mmol) at ꢀ78 ꢂC under N2 atmosphere. The reaction
mixture was stirred for 1 h at ꢀ78 ꢂC and then allowed
to warm to room temperature overnight. The reaction
mixture was poured into water and extracted with
dichloromethane. The extract was dried over anhydrous
magnesium sulfate, concentrated, and purified with
5.20. (3RS,4RS)-7-Methoxy-3-(4-methoxyphenyl)-3-
methyl-4-[10-(4,4,5,5,5-pentafluoropentylsulfanyl)-
decyl]thiochroman (11c) and (3RS,4SR)-7-Methoxy-3-(4-
methoxyphenyl)-3-methyl-4-[10-(4,4,5,5,5-penta-
fluoropentylsulfanyl)decyl]thiochroman (12c)
These compounds, 11c (79%) and 12c (13%), were pre-
pared from 10c (3RS,4RS/3RS,4SR = 7:l) and 5a using
a procedure similar to that described for 11b and 12b.
column
chromatography
(n-hexane/ethyl
ace-
tate = 50:1 ! 5:1) to afford 85 mg (74%) of 13b. 1H
NMR (400 MHz, CDCl3) d: 7.24 (2H, d, J = 8.1 Hz,
ArH), 6.87 (1H, d, J = 8.3 Hz, ArH), 6.83 (2H, d,
J = 8.1 Hz, ArH), 6.67 (1H, s, ArH), 6.50 (1H, d,
J = 8.3 Hz, ArH), 4.86 (1H, br s, OH), 4.68 (1H, br s,
OH), 3.62 (1H, d, J = 11.4 Hz, H-2), 2.96 (1H, d,
1H NMR (11c, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.4 Hz, ArH), 6.94–6.90 (3H, m, ArH), 6.73 (1H,
s, ArH), 6.58 (1H, d, J = 8.1 Hz, ArH), 3.82 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.64 (1H, d, J = 11.5 Hz,
H-2), 2.99 (1H, d, J = 11.5 Hz, H-2), 2.73 (1H, br s,

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4813
J = 11.4 Hz, H-2), 2.70 (1H, br s, H-4), 2.58 (2H, t,
J = 7.1 Hz, CH2S), 2.48 (2H, t, J = 7.3 Hz, CH2S),
2.23–2.10 (2H, m, CH2CH2CF2CF3), 1.92–1.84 (2H,
m, CH2CH2CF2CF3), 1.57–1.07 (19H, m, (CH2)8CH2S
and C3-CH3); HRMS (ES-NEG) calculated for
C30H39F5O2S2: 589.2233. Found: 589.2243 (+1.6 ppm).
over anhydrous magnesium sulfate and concentrated.
The crude product was purified with column chromatog-
raphy (n-hexane/ethyl acetate = 5:1 ! 1:1) to afford
29 mg (86%) of 14b. 1H NMR (400 MHz, CDCl3 + D2O)
d: 7.23–7.20 (2H, m, ArH), 6.87–6.83 (3H, m, ArH), 6.67
(1H, d, J = 2.6 Hz, ArH), 6.52–6.49 (1H, m, ArH), 3.67–
3.63 (1H, m, H-2), 2.96–2.61 (6H, m, H-2, H-4, and
CH2SOCH2), 2.32–2.17 (4H, m, CH2CH2CF2CF3),
1.80–1.01 (19H, m, (CH2)8CH2SO and C3-CH3); HRMS
(ES-POS) calculated for C30H39F5O3S2: 607.2339.
Found: 607.2345 (+1.0 ppm).
5.23. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[8-(4,4,5,5,5-pentafluoropentylsulfanyl)octyl]thio-
chroman-7-ol (13a)
This compound was prepared from 11a using a proce-
dure similar to that described for 13b. 1H NMR
(400 MHz, CDCl3) d: 7.24 (2H, d, J = 8.4 Hz, ArH),
6.87 (1H, d, J = 8.2 Hz, ArH), 6.83 (2H, d, J = 8.4 Hz,
ArH), 6.67 (1H, s, ArH), 6.50 (1H, d, J = 8.2 Hz,
ArH), 4.91 (1H, br s, OH), 4.68 (1H, br s, OH), 3.63
(1H, d, J = 11.4 Hz, H-2), 2.96 (1H, d, J = 11.4 Hz, H-
2), 2.70 (1H, br s, H-4), 2.58 (2H, t, J = 7.0 Hz,
CH2S), 2.46 (2H, t, J = 7.3 Hz, CH2S), 2.17–2.14
(2H, m, CH2CH2CF2CF3), 1.89–1.86 (2H, m,
CH2CH2CF2CF3), 1.56–1.07 (17H, m, (CH2)7CH2S
and C3-CH3); MS (m/z) 577 (M+1).
5.27. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[8-(4,4,5,5,5-pentafluoropentylsulfinyl)octyl]thio-
chroman-7-ol (14a)
This compound was prepared from 13a using a procedure
similar to that described for 14b. H NMR (400 MHz,
1
CDCl3 + D2O) d: 7.22 (2H, d, J = 8.8 Hz, ArH), 6.87–
6.85 (3H, m, ArH), 6.67 (1H, d, J = 2.6 Hz, ArH), 6.50
(1H, dd, J = 8.1, 2.6 Hz, ArH), 3.65 (1H, d, J = 11.4 Hz,
H-2), 2.94 (1H, d, J = 11.4 Hz, H-2), 2.90–2.56 (5H, m,
CH2SOCH2
and
H-4),
2.33–2.16
(4H,
m,
CH2CH2CF2CF3), 1.69–0.91 (17H, m, (CH2)7CH2SO
and C3-CH3); HRMS (ES-POS) calculated for
C29H37F5O3S2: 593.2183. Found: 593.2175 (ꢀ1.3 ppm).
5.24. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[10-(4,4,5,5,5-pentafluoropentylsulfanyl)decyl]thio-
chroman-7-ol (13c)
5.28. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[10-(4,4,5,5,5-pentafluoropentylsulfinyl)decyl]thio-
chroman-7-ol (14c)
This compound was prepared from 11c using a proce-
dure similar to that described for 13b. 1H NMR
(400 MHz, CDCl3) d: 7.24 (2H, d, J = 7.7 Hz, ArH),
6.88 (1H, d, J = 8.1 Hz, ArH), 6.83 (2H, d, J = 7.7 Hz,
ArH), 6.67 (1H, s, ArH), 6.50 (1H, d, J = 8.1 Hz,
ArH), 4.90 (1H, br s, OH), 4.72 (1H, br s, OH), 3.62
(1H, d, J = 11.7 Hz, H-2), 2.96 (1H, d, J = 11.7 Hz, H-
2), 2.71 (1H, br s, H-4), 2.59 (2H, t, J = 7.0 Hz,
CH2S), 2.50 (2H, t, J = 7.3 Hz, CH2S), 2.23–2.10
(2H, m, CH2CH2CF2CF3), 1.92–1.84 (2H, m,
CH2CH2CF2CF3), 1.61–1.07 (21H, m, (CH2)9CH2S
and C3-CH3); MS (m/z) 605 (M+1).
This compound was prepared from 13c using a proce-
dure similar to that described for 14b. 1H NMR
(400 MHz, CDCl3 + D2O) d: 7.21 (2H, d, J = 8.8 Hz,
ArH), 6.87–6.83 (3H, m, ArH), 6.67 (1H, d,
J = 1.8 Hz, ArH), 6.51–6.49 (1H, m, ArH), 3.66–3.62
(1H, m, H-2), 2.96–2.64 (6H, m, H-2, H-4, and
CH2SOCH2), 2.31–2.18 (4H, m, CH2CH2CF2CF3),
1.82–0.97 (21H, m, (CH2)9CH2SO and C3-CH3);
HRMS (ES-POS) calculated for C31H41F5O3S2:
621.2496. Found: 621.2473 (ꢀ3.6 ppm).
5.25. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(pentylsulfanyl)nonyl]thiochroman-7-ol (13d)
5.29. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(pentylsulfinyl)nonyl]thiochroman-7-ol (14d)
This compound was prepared from 11d using a procedure
similar to that described for 13b. H NMR (400 MHz,
1
This compound was prepared from 13d using a proce-
dure similar to that described for 14b. 1H NMR
(400 MHz, CDCl3 + D2O) d: 7.22–7.20 (2H, m, ArH),
6.87–6.84 (3H, m, ArH), 6.67 (1H, d, J = 2.6 Hz,
ArH), 6.53–6.49 (1H, m, ArH), 3.67–3.63 (1H, m, H-
2), 2.96–2.58 (6H, m, H-2, H-4, and CH2SOCH2),
CDCl3) d: 7.22 (2H, d, J = 7.7 Hz, ArH), 6.87 (1H, d,
J = 8.2 Hz, ArH), 6.84 (2H, d, J = 7.7 Hz, ArH), 6.67
(1H, s, ArH), 6.50 (1H, d, J = 8.2 Hz, ArH), 4.99 (1H,
br s, OH), 4.71 (1H, br s, OH), 3.63 (1H, d, J = 11.5 Hz,
H-2), 2.96 (1H, d, J = 11.5 Hz, H-2), 2.70 (1H, br s,
H-4), 2.52–2.48 (4H, m, CH2SCH2), 1.56–0.88 (28H, m,
(CH2)8CH2SCH2(CH 2)3CH3 and C3-CH3).
1.82–0.91 (28H, m, (CH2)8CH2SOCH2(CH ) CH3 and
2 3
C3-CH3);
HRMS
(ES-POS)
calculated
for
C30H44O3S2: 517.2810. Found: 517.2806 (ꢀ0.8 ppm).
5.26. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thio-
chroman-7-ol (14b)
5.30. (3RS,4SR)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]thio-
chroman-7-ol (15b)
To a stirred mixture of 13b (33 mg, 0.056 mmol) and Ox-
one (21 mg, 0.034 mmol) in tetrahydrofuran (10 mL) was
added water (1 mL) and stirred for 10 min at room tem-
perature. The reaction mixture was poured into water
and extracted with ethyl acetate. The extract was dried
This compound was prepared from 12b using a proce-
dure similar to that described for 13b. 1H NMR
(400 MHz, CDCl3) d: 7.25 (2H, d, J = 8.4 Hz, ArH),
6.68 (1H, d, J = 8.1 Hz, ArH), 6.62 (2H, d, J = 8.4 Hz,

4814
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
ArH), 6.47 (1H, s, ArH), 6.32 (1H, d, J = 8.1 Hz, ArH),
4.56 (1H, br s, OH), 4.49 (1H, br s, OH), 3.23 (2H, s, H-
2), 2.88 (1H, br s, H-4), 2.59 (2H, t, J = 7.0 Hz, CH2S),
2.50 (2H, t, J = 7.3 Hz, CH2S), 2.24–2.10 (2H, m,
CH2CH2CF2CF3), 1.92–1.84 (2H, m, CH2CH2CF2CF3),
1.66–1.24 (19H, m, (CH2)8CH2S and C3-CH3); HRMS
(ES-NEG) calculated for C30H39F5O2S2: 589.2233.
Found: 589.2240 (+1.1 ppm).
(1H, d, J = 10.4 Hz, H-2), 3.60 (2H, t, J = 6.8 Hz,
CH2OTBS), 3.50 (3H, s, OCH3), 3.47 (3H, s, OCH3),
2.26 (2H, t, J = 7.0 Hz, CꢁCCH2), 2.05 (1H, s, OH),
1.58–1.22 (15H, m, C3-CH3 and (CH2)6CH2OTBS),
0.89 (9H, s, TBS), 0.04 (6H, s, TBS).
5.34. 4-[9-(t-Butyldimethylsilyloxy)nonyl]-7-methoxy-
methyloxy-3-[4-(methoxymethyloxy)phenyl-3-methyl-
chroman (18b) and 9-[7-Methoxymethyloxy-3-
(4-methoxymethyloxy)phenyl-3-methylchroman-4-yl]-
nonan-1-ol (19b)
5.31. 4-[9-(tert-Butyldimethylsilyloxy)-non-1-ynyl]-7-
methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-
methylchroman-4-ol (17b)
A mixture of 17b (756 mg, 1.23 mmol) and 10% Pd/C
(110 mg, ACROS) in ethyl acetate (40 mL) was stirred
at room temperature for 7 h under hydrogen atmo-
sphere. Then, the reaction mixture was filtered to re-
move 10% Pd/C and concentrated. The crude product
was purified with column chromatography (n-hexane/
ethyl acetate = 10:1 ! 2:1) to afford 309 mg (51%,
To a tetrahydrofuran solution (10 mL) of 3b (1.58 g,
6.21 mmol) was added a 2.70 M hexane solution of n-bu-
tyl lithium (2.0 mL, 5.4 mmol) at ꢀ20 ꢂC under N2 atmo-
sphere, and the reaction mixture was stirred for 1 h at
ꢀ20 ꢂC. Then a tetrahydrofuran solution (10 mL) of 16
(0.97 g, 2.71 mmol) was added to the reaction mixture
and stirred 2 h at ꢀ10 ꢂC. The reaction mixture was
poured into water and extracted with ethyl acetate. The
extract was dried over anhydrous magnesium sulfate,
concentrated and purified with column chromatography
(n-hexane/ethyl acetate = 10:1 ! 5:1) to afford 1.61 g
3RS,4RS/3RS,4SR = 5:l)
of
18b
and
106 mg
(18%,3RS,4RS/3RS,4SR = 1:l) of 19b.
1H NMR (18b, 400 MHz, CDCl3) d: 7.30–6.94 (5H, m,
ArH of cis- and trans-isomer), 6.58–6.48 (2H, m, ArH
of cis- and trans-isomer), 5.18 (10/6H, s, OCH2OCH3 of
cis-isomer), 5.15 (10/6H, s, OCH2OCH3 of cis-isomer),
5.14 (2/6H, s, OCH2OCH3 of trans-isomer), 5.11 (2/6H,
s, OCH2OCH3 of trans-isomer), 4.52 (5/6H, d,
J = 10.3 Hz, H-2 of cis-isomer), 4.27–4.21 (1H, m, H-2
of cis- and trans-isomer), 3.93 (1/6H, d, J = 11.0 Hz, H-
2 of trans-isomer), 3.60–3.55 (2H, m, CH2OTBS of cis-
and trans-isomer), 3.50 (15/6H, s, OCH3 of cis-isomer),
3.49 (15/6H, s, OCH3 of cis-isomer), 3.47 (3/6H, s,
OCH3 of trans-isomer), 3.46 (3/6H, s, OCH3 of trans-
isomer), 3.04 (1/6H, br s, H-4 of trans-isomer), 2.65 (5/
6H, br s, H-4 of cis-isomer), 1.53–1.07 (19H, m, C3-CH3
and (CH2)8CH2OTBS of cis- and trans-isomer), 0.89 (9/
6H, s, TBS of trans-isomer), 0.88 (45/6H, s, TBS of cis-
isomer), 0.04 (6/6H, s, TBS of trans-isomer), 0.03 (30/
6H, s, TBS of cis-isomer).
1
(97%) of 17b. H NMR (400 MHz, CDCl3) d: 7.66 (1H,
d, J = 8.8 Hz, ArH), 7.48 (2H, d, J = 9.0 Hz, ArH), 7.05
(2H, d, J = 9.0 Hz, ArH), 6.67 (1H, dd, J = 8.8, 2.6 Hz,
ArH), 6.56 (1H, d, J = 2.6 Hz, ArH), 5.19 (2H, s,
OCH2OCH3), 5.16 (2H, s, OCH2OCH3), 4.91 (1H, d,
J = 10.4 Hz, H-2), 4.06 (1H, d, J = 10.4 Hz, H-2), 3.60
(2H, t, J = 6.6 Hz, CH2OTBS), 3.50 (3H, s, OCH3), 3.47
(3H, s, OCH3), 2.26 (2H, t, J = 7.0 Hz, CꢁCCH2), 2.05
(1H, s, OH), 1.58–1.32 (13H, m, C3-CH3 and
(CH2)5CH2OTBS), 0.89 (9H, s, TBS), 0.05 (6H, s, TBS).
5.32. 4-[8-(tert-Butyldimethylsilyloxy)-oct-1-ynyl]-7-
methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-
methylchroman-4-ol (17a)
This compound was prepared from 16 and 3a using a pro-
cedure similar to that described for 17b. 1H NMR
(400 MHz, CDCl3) d: 7.66 (1H, d, J = 8.8 Hz, ArH),
7.48 (2H, d, J = 9.0 Hz, ArH), 7.05 (2H, d, J = 9.0 Hz,
ArH), 6.67 (1H, dd, J = 8.8, 2.6 Hz, ArH), 6.56 (1H, d,
J = 2.6 Hz, ArH), 5.19 (2H, s, OCH2OCH3), 5.16 (2H,
s, OCH2OCH3), 4.91 (1H, d, J = 10.4 Hz, H-2), 4.06
(1H, d, J = 10.4 Hz, H-2), 3.61 (2H, t, J = 6.4 Hz,
CH2OTBS), 3.50 (3H, s, OCH3), 3.47 (3H, s, OCH3),
2.27 (2H, t, J = 7.0 Hz, CꢁCCH2), 2.05 (1H, s, OH),
1.59–1.35 (11H, m, C3-CH3 and (CH2)4CH2OTBS),
0.89 (9H, s, TBS), 0.05 (6H, s, TBS).
1H NMR (19b, 400 MHz, CDCl3) d: 7.30–6.94 (5H, m,
ArH of cis- and trans-isomer), 6.58–6.48 (2H, m, ArH
of cis- and trans-isomer), 5.18 (2/2H, s, OCH2OCH3 of
cis-isomer), 5.15 (2H, s, OCH2OCH3 of cis- and trans-
isomer), 5.11 (2/2H, s, OCH2OCH3 of trans-isomer),
4.52 (1/2H, d, J = 10.6 Hz, H-2 of cis-isomer), 4.28–
4.21 (1H, m, H-2 of cis- and trans-isomer), 3.93 (1/2H,
d, J = 11.0 Hz, H-2 of trans-isomer), 3.67–3.59 (2H, m,
CH2OH of cis- and trans-isomer), 3.50 (3/2H, s, OCH3
of cis-isomer), 3.49 (3/2H, s, OCH3 of cis-isomer), 3.47
(3/2H, s, OCH3 of trans-isomer), 3.46 (3/2H, s, OCH3
of trans-isomer), 3.05 (1/2H, br s, H-4 of trans-isomer),
2.65 (1/2H, br s, H-4 of cis-isomer), 1.54–1.07 (19H,
m, C3-CH3 and (CH2)8CH2OH of cis- and trans-
isomer).
5.33. 4-[10-(tert-Butyldimethylsilyloxy)-dec-1-ynyl]-7-
methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-
methylchroman-4-ol (17c)
This compound was prepared from 16 and 3c using a
procedure similar to that described for 17b. H NMR
1
5.35. 4-[8-(t-Butyldimethylsilyloxy)octyl]-7-methoxy-
methyloxy-3-[4-(methoxymethyloxy)phenyl-3-methyl-
chroman (18a)
(CDCl3) d: 7.66 (1H, d, J = 8.4 Hz, ArH), 7.48 (2H, d,
J = 9.0 Hz, ArH), 7.05 (2H, d, J = 9.0 Hz, ArH), 6.67
(1H, dd, J = 8.4, 2.6 Hz, ArH), 6.56 (1H, d,
J = 2.6 Hz, ArH), 5.19 (2H, s, OCH2OCH3), 5.16 (2H,
s, OCH2OCH3), 4.91 (1H, d, J = 10.4 Hz, H-2), 4.06
A mixture of 17a (550 mg, 0.92 mmol) and 10% Pd/C
(50 mg, ACROS) in ethyl acetate (30 mL) was stirred

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4815
at room temperature for 45 min under hydrogen atmo-
sphere. Then, the reaction mixture was filtered to re-
move 10% Pd/C and concentrated. The crude product
was purified with column chromatography (n-hexane/
ethyl acetate = 10:1) to afford 423 mg (78%, 3RS,4RS/
trans-isomer), 5.11 (2/6H, s, OCH2OCH3 of trans-iso-
mer), 4.52 (5/6H, d, J = 10.6 Hz, H-2 of cis-isomer),
4.28–4.21 (1H, m, H-2 of cis- and trans-isomer), 3.93
(1/6H, d, J = 11.0 Hz, H-2 of trans-isomer), 3.67–3.59
(2H, m, CH2OH of cis- and trans-isomer), 3.50 (15/
6H, s, OCH3 of cis-isomer), 3.49 (15/6H, s, OCH3 of
cis-isomer), 3.47 (3/6H, s, OCH3 of trans-isomer), 3.46
(3/6H, s, OCH3 of trans-isomer), 3.05 (1/6H, br s, H-4
of trans-isomer), 2.65 (5/6H, br s, H-4 of cis-isomer),
1.54–1.07 (19H, m, C3-CH3 and (CH2)8CH2OH of cis-
and trans-isomer).
1
3RS,4SR = 2:l) of 18a. H NMR (400 MHz, CDCl3) d:
7.30–6.94 (5H, m, ArH of cis- and trans-isomer), 6.58–
6.48 (2H, m, ArH of cis- and trans-isomer), 5.18 (4/
3H, s, OCH2OCH3 of cis-isomer), 5.15 (4/3H, s,
OCH2OCH3 of cis-isomer), 5.14 (2/3H, s, OCH2OCH3
of trans-isomer), 5.11 (2/3H, s, OCH2OCH3 of trans-iso-
mer), 4.52 (2/3H, d, J = 10.3 Hz, H-2 of cis-isomer),
4.27–4.21 (1H, m, H-2 of cis- and trans-isomer), 3.93
(1/3H, d, J = 11.0 Hz, H-2 of trans-isomer), 3.60–3.54
(2H, m, CH2OTBS of cis- and trans-isomer), 3.50 (6/
3H, s, OCH3 of cis-isomer), 3.49 (6/3H, s, OCH3 of
cis-isomer), 3.47 (3/3H, s, OCH3 of trans-isomer), 3.46
(3/3H, s, OCH3 of trans-isomer), 3.04 (1/3H, br s, H-4
of trans-isomer), 2.65 (2/3H, br s, H-4 of cis-isomer),
1.53–1.07 (17H, m, C3-CH3 and (CH2)7CH2OTBS of
cis- and trans-isomer), 0.89 (9/3H, s, TBS of trans-iso-
mer), 0.88 (18/3H, s, TBS of cis-isomer), 0.04 (6/3H, s,
TBS of trans-isomer), 0.03 (12/3H, s, TBS of cis-isomer).
5.38. 8-[7-Methoxymethyloxy-3-(4-methoxymethyl-
oxy)phenyl-3-methylchroman-4-yl]-octan-1-ol (19a)
This compound (3RS,4RS/3RS,4SR = 2:l) was prepared
from 18a (3RS,4RS/3RS,4SR = 2:l) using a procedure
similar to that described for 19b. H NMR (400 MHz,
1
CDCl3) d: 7.30–6.94 (5H, m, ArH of cis- and trans-iso-
mer), 6.58–6.48 (2H, m, ArH of cis- and trans-isomer),
5.18 (4/3H, s, OCH2OCH3 of cis-isomer), 5.15 (4/3H,
s, OCH2OCH3 of cis-isomer), 5.14 (2/3H, s, OCH2OCH3
of trans-isomer), 5.11 (2/3H, s, OCH2OCH3 of trans-iso-
mer), 4.52 (2/3H, d, J = 10.6 Hz, H-2 of cis-isomer),
4.28–4.21 (1H, m, H-2 of cis- and trans-isomer), 3.93
(1/3H, d, J = 11.0 Hz, H-2 of trans-isomer), 3.65–3.57
(2H, m, CH2OH of cis- and trans-isomer), 3.50 (6/3H,
s, OCH3 of cis-isomer), 3.49 (6/3H, s, OCH3 of cis-iso-
mer), 3.47 (3/3H, s, OCH3 of trans-isomer), 3.46 (3/
3H, s, OCH3 of trans-isomer), 3.05 (1/3H, br s, H-4 of
trans-isomer), 2.64 (2/3H, br s, H-4 of cis-isomer),
1.54–1.07 (17H, m, C3-CH3 and (CH2)7CH2OH of cis-
and trans-isomer).
5.36. 4-[10-(t-Butyldimethylsilyloxy)decyl]-7-methoxy-
methyloxy-3-[4-(methoxymethyloxy)phenyl-3-methyl-
chroman (18c)
This compound (3RS,4RS/3RS,4SR = 5:2) was pre-
pared from 17c using a procedure similar to that de-
1
scribed for 18a. H NMR (400 MHz, CDCl3) d: 7.30–
6.94 (5H, m, ArH of cis- and trans-isomer), 6.57–6.48
(2H, m, ArH of cis- and trans-isomer), 5.18 (10/7H, s,
OCH2OCH3 of cis-isomer), 5.15 (10/7H, s, OCH2OCH3
of cis-isomer), 5.14 (4/7H, s, OCH2OCH3 of trans-iso-
mer), 5.11 (4/7H, s, OCH2OCH3 of trans-isomer), 4.52
(5/7H, d, J = 10.3 Hz, H-2 of cis-isomer), 4.27–4.21
(1H, m, H-2 of cis- and trans-isomer), 3.93 (2/7H, d,
J = 11.0 Hz, H-2 of trans-isomer), 3.61–3.56 (2H, m,
CH2OTBS of cis- and trans-isomer), 3.50 (15/7H, s,
OCH3 of cis-isomer), 3.49 (15/7H, s, OCH3 of cis-iso-
mer), 3.47 (6/7H, s, OCH3 of trans-isomer), 3.46 (6/
7H, s, OCH3 of trans-isomer), 3.04 (2/7H, br s, H-4 of
trans-isomer), 2.65 (5/7H, br s, H-4 of cis-isomer),
1.52–1.09 (21H, m, C3-CH3 and (CH2)9CH2OTBS of
cis- and trans-isomer), 0.89 (18/7H, s, TBS of trans-iso-
mer), 0.88 (45/7H, s, TBS of cis-isomer), 0.05 (12/7H, s,
TBS of trans-isomer), 0.04 (30/7H, s, TBS of cis-isomer).
5.39. 10-[7-Methoxymethyloxy-3-(4-methoxymethyl-
oxy)phenyl-3-methylchroman-4-yl]-decan-1-ol (19c)
This compound (3RS,4RS/3RS,4SR = 5:2) was pre-
pared from 18c (3RS,4RS/3RS,4SR = 5:2) using a pro-
cedure similar to that described for 19b. 1H NMR
(400 MHz, CDCl3) d: 7.30–6.94 (5H, m, ArH of cis-
and trans-isomer), 6.58–6.48 (2H, m, ArH of cis- and
trans-isomer), 5.18 (10/7H, s, OCH2OCH3 of cis-iso-
mer), 5.15 (10/7H, s, OCH2OCH3 of cis-isomer), 5.14
(4/7H, s, OCH2OCH3 of trans-isomer), 5.11 (4/7H, s,
OCH2OCH3 of trans-isomer), 4.52 (5/7H, d,
J = 10.6 Hz, H-2 of cis-isomer), 4.27–4.21 (1H, m, H-2
of cis- and trans-isomer), 3.93 (2/7H, d, J = 11.4 Hz,
H-2 of trans-isomer), 3.63 (2H, br s, CH2OH of cis-
and trans-isomer), 3.50 (15/7H, s, OCH3 of cis-isomer),
3.49 (15/7H, s, OCH3 of cis-isomer), 3.47 (6/7H, s,
OCH3 of trans-isomer), 3.46 (6/7H, s, OCH3 of trans-
isomer), 3.04 (2/7H, br s, H-4 of trans-isomer), 2.65
(5/7H, br s, H-4 of cis-isomer), 1.57–1.07 (21H, m,
C3-CH3 and (CH2)9CH2OH of cis- and trans-isomer).
5.37. 9-[7-Methoxymethyloxy-3-(4-methoxymethyl-
oxy)phenyl-3-methylchroman-4-yl]-nonan-1-ol (19b)
A mixture of 18b (138 mg, 0.23 mmol, 3RS,4RS/
3RS,4SR = 5:l) and pyridinium p-toluenesulfonate
(140 mg) in methanol (5 mL) and dichloromethane
(2 mL) was stirred at room temperature for 2 h. Then,
the reaction mixture was concentrated, and purified with
column chromatography (n-hexane/ethyl acetate = 2:1)
to afford 102 mg (91%, 3RS,4RS/3RS,4SR = 5:l) of
5.40. 8-[7-Methoxymethyloxy-3-(4-methoxymethyl-
oxy)phenyl-3-methylchroman-4-yl]octyl methanesulfonate
(20a)
1
19b. H NMR (400 MHz, CDCl3) d: 7.30–6.94 (5H, m,
ArH of cis- and trans-isomer), 6.58–6.48 (2H, m, ArH
of cis- and trans-isomer), 5.18 (10/6H, s, OCH2OCH3
of cis-isomer), 5.15 (2H, s, OCH2OCH3 of cis- and
This compound (3RS,4RS/3RS,4SR = 2:1) was pre-
pared from 19a (3RS,4RS/3RS,4SR = 2:1) using a
procedure similar to that described for 10b. H NMR
1

4816
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
(400 MHz, CDCl3) d: 7.30–6.93 (5H, m, ArH of cis- and
trans-isomer), 6.58–6.48 (2H, m, ArH of cis- and trans-
isomer), 5.18 (4/3H, s, OCH2OCH3 of cis-isomer), 5.15
(4/3H, s, OCH2OCH3 of cis-isomer), 5.14 (2/3H, s,
OCH2OCH3 of trans-isomer), 5.11 (2/3H, s, OCH2OCH3
of trans-isomer), 4.52 (2/3H, d, J = 10.6 Hz, H-2 of cis-
isomer), 4.28–4.18 (3H, m, H-2 and CH2OMs of cis-
and trans-isomer), 3.93 (1/3H, d, J = 11.0 Hz, H-2 of
trans-isomer), 3.50 (6/3H, s, OCH3 of cis-isomer), 3.49
(6/3H, s, OCH3 of cis-isomer), 3.47 (3/3H, s, OCH3 of
trans-isomer), 3.46 (3/3H, s, OCH3 of trans-isomer),
3.04 (1/3H, br s, H-4 of trans-isomer), 3.00 (3/3H, s,
OMs of trans-isomer), 2.98 (6/3H, s, OMs of cis-isomer),
2.64 (2/3H, br s, H-4 of cis-isomer), 1.72–1.07 (17H, m,
C3-CH3 and (CH2)7CH2OMs of cis- and trans-isomer).
5.43. (3RS,4RS)-7-Methoxymethyloxy-3-(4-methoxym-
ethyloxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-penta-
fluoropentylsulfanyl)octyl]chroman (21a) and (3RS,4SR)-
7-methoxy-methyloxy-3-(4-methoxymethyloxyphenyl)-3-
methyl-4-[8-(4,4,5,5,5-pentafluoropentyl-sulfanyl)oc-
tyl]chroman (22a)
These compounds, 21a (59%) and 22a (19%), were pre-
pared from 20a (3RS,4RS/3RS,4SR = 2:l) and 5a using
a procedure similar to that described for 11b and 12b.
1H NMR (21a, 400 MHz, CDCl3) d: 7.13 (2H, d,
J = 8.8 Hz, ArH), 7.03 (2H, d, J = 8.8 Hz, ArH), 6.96–
6.93 (1H, m, ArH), 6.57–6.55 (2H, m, ArH), 5.18 (2H,
s, OCH2OCH3), 5.15 (2H, s, OCH2OCH3), 4.52 (1H,
d, J = 10.6 Hz, H-2), 4.26 (1H, d, J = 10.6 Hz, H-2),
3.50 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.65 (1H, br
s, H-4), 2.57 (2H, t, J = 7.1 Hz, CH2S), 2.46 (2H, t,
5.41. 9-[7-Methoxymethyloxy-3-(4-methoxymethyl-
oxy)phenyl-3-methylchroman-4-yl]nonyl methanesulfo-
nate (20b)
J = 7.5 Hz,
CH2S),
2.22–2.09
(2H,
m,
CH2CH2CF2CF3), 1.90–1.83 (2H, m, CH2CH2CF2CF3),
1.56–1.02 (17H, m, C3-CH3 and (CH2)7CH2S); MS
(m/z) 649 (M+1).
This compound (3RS,4RS/3RS,4SR = 3:1) was prepared
from 19b (3RS,4RS/3RS,4SR = 3:1) using a procedure
similar to that described for 10b. H NMR (400 MHz,
1
1H NMR (22a, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.8 Hz, ArH), 7.01 (1H, d, J = 8.8 Hz, ArH), 6.96
(2H, d, J = 8.8 Hz, ArH), 6.54–6.48 (2H, m, ArH),
5.14 (2H, s, OCH2OCH3), 5.11 (2H, s, OCH2OCH3),
4.22 (1H, d, J = 11.2 Hz, H-2), 3.93 (1H, d,
J = 11.2 Hz, H-2), 3.47 (3H, s, OCH3), 3.46 (3H, s,
OCH3), 3.04 (1H, br s, H-4), 2.58 (2H, t, J = 7.0 Hz,
CH2S), 2.49 (2H, t, J = 7.3 Hz, CH2S), 2.22–2.10 (2H,
CDCl3) d: 7.30–6.93 (5H, m, ArH of cis- and trans-iso-
mer), 6.58–6.48 (2H, m, ArH of cis- and trans-isomer),
5.18 (6/4H, s, OCH2OCH3 of cis-isomer), 5.15 (6/4H, s,
OCH2OCH3 of cis-isomer), 5.14 (2/4H, s, OCH2OCH3
of trans-isomer), 5.11 (2/4H, s, OCH2OCH3 of trans-iso-
mer), 4.52 (3/4H, d, J = 10.3 Hz, H-2 of cis-isomer), 4.28–
4.18 (3H, m, H-2 and CH2OMs of cis- and trans-isomer),
3.93 (1/4H, d, J = 11.0 Hz, H-2 of trans-isomer), 3.50 (9/
4H, s, OCH3 of cis-isomer), 3.49 (9/4H, s, OCH3 of cis-
isomer), 3.47 (3/4H, s, OCH3 of trans-isomer), 3.46 (3/
4H, s, OCH3 of trans-isomer), 3.04 (1/4H, br s, H-4 of
trans-isomer), 3.00 (3/4H, s, OMs of trans-isomer), 2.99
(9/4H, s, OMs of cis-isomer), 2.65 (3/4H, br s, H-4 of
cis-isomer), 1.72–1.07 (19H, m, C3-CH3 and
(CH2)8CH2OMs of cis- and trans-isomer).
m,
CH2CH2CF2CF3),
1.92–1.84
(2H,
m,
CH2CH2CF2CF3), 1.59–1.21 (17H, m, C3-CH3 and
(CH2)7CH2S); MS (m/z) 649 (M+1).
5.44. (3RS,4RS)-7-Methoxymethyloxy-3-(4-methoxy-
methyloxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-penta-
fluoropentylsulfanyl)nonyl]chroman (21b) and
(3RS,4SR)-7-Methoxymethyloxy-3-(4-methoxymethyl-
oxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentyl-
sulfanyl)nonyl]chroman (22b)
5.42. 10-[7-Methoxymethyloxy-3-(4-methoxymethyl-
oxy)phenyl-3-methylchroman-4-yl]decyl methanesulfo-
nate (20c)
These compounds, 21b (54%) and 22b (10%), were pre-
pared from 20b (3RS,4RS/3RS,4SR = 3:l) and 5a using
a procedure similar to that described for 11b and 12b.
This compound (3RS,4RS/3RS,4SR = 3:1) was pre-
pared from 19c (3RS,4RS/3RS,4SR = 3:1) using a pro-
cedure similar to that described for 10b. 1H NMR
(400 MHz, CDCl3) d: 7.30–6.94 (5H, m, ArH of cis-
and trans-isomer), 6.58–6.48 (2H, m, ArH of cis- and
trans-isomer), 5.18 (6/4H, s, OCH2OCH3 of cis-isomer),
5.15 (6/4H, s, OCH2OCH3 of cis-isomer), 5.14 (2/4H, s,
OCH2OCH3 of trans-isomer), 5.11 (2/4H, s,
OCH2OCH3 of trans-isomer), 4.52 (3/4H, d,
J = 10.6 Hz, H-2 of cis-isomer), 4.28–4.19 (3H, m, H-2
and CH2OMs of cis- and trans-isomer), 3.93 (1/4H,
d, J = 11.0 Hz, H-2 of trans-isomer), 3.50 (9/4H, s,
OCH3 of cis-isomer), 3.49 (9/4H, s, OCH3 of cis-iso-
mer), 3.47 (3/4H, s, OCH3 of trans-isomer), 3.46 (3/
4H, s, OCH3 of trans-isomer), 3.04 (1/4H, br s, H-4
of trans-isomer), 3.00 (3/4H, s, OMs of trans-isomer),
2.99 (9/4H, s, OMs of cis-isomer), 2.65 (3/4H, br s, H-
4 of cis-isomer), 1.76–1.02 (21H, m, C3-CH3 and
(CH2)9CH2OMs of cis- and trans-isomer).
1H NMR (21b, 400 MHz, CDCl3) d: 7.13 (2H, d,
J = 8.8 Hz, ArH), 7.02 (2H, d, J = 8.8 Hz, ArH), 6.96–
6.93 (1H, m, ArH), 6.57–6.55 (2H, m, ArH), 5.18 (2H,
s, OCH2OCH3), 5.15 (2H, s, OCH2OCH3), 4.52 (1H,
d, J = 10.3 Hz, H-2), 4.26 (1H, d, J = 10.3 Hz, H-2),
3.50 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.64 (1H, br
s, H-4), 2.57 (2H, t, J = 7.0 Hz, CH2S), 2.48 (2H, t,
J = 7.3 Hz,
CH2S),
2.21–2.09
(2H,
m,
CH2CH2CF2CF3), 1.91–1.83 (2H, m, CH2CH2CF2CF3),
1.58–1.01 (19H, m, C3-CH3 and (CH2)8CH2S); MS
(m/z) 663 (M+1).
1H NMR (22b, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.8 Hz, ArH), 7.01 (1H, d, J = 8.4 Hz, ArH), 6.96
(2H, d, J = 8.8 Hz, ArH), 6.54–6.48 (2H, m, ArH),
5.14 (2H, s, OCH2OCH3), 5.11 (2H, s, OCH2OCH3),
4.22 (1H, d, J = 11.4 Hz, H-2), 3.93 (1H, d,

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4817
J = 11.4 Hz, H-2), 3.47 (3H, s, OCH3), 3.46 (3H, s,
5.47. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-[8-
(4,4,5,5,5-pentafluoropentylsulfanyl)octyl]chroman-7-ol
(23a)
OCH3), 3.04 (1H, br s, H-4), 2.59 (2H, t, J = 7.0 Hz,
CH2S), 2.50 (2H, t, J = 7.3 Hz, CH2S), 2.24–2.10 (2H,
m, CH2CH2CF2CF3), 1.92–1.84 (2H, m, CH2CH2CF2
CF3), 1.60–1.20 (19H, m, C3-CH3 and (CH2)8CH2S);
MS (m/z) 663 (M+1).
This compound was prepared from 21a using a procedure
similar to that described for 23b. H NMR (400 MHz,
1
CDCl3) d: 7.08 (2H, d, J = 8.6 Hz, ArH), 6.89 (1H, d,
J = 8.1 Hz, ArH), 6.83 (2H, d, J = 8.6 Hz, ArH), 6.39–
6.35 (2H, m, ArH), 5.07 (1H, br s, OH), 4.75 (1H, br s,
OH), 4.51 (1H, d, J = 10.3 Hz, H-2), 4.24 (1H, d,
J = 10.3 Hz, H-2), 2.61–2.56 (3H, m, H-4 and CH2S),
2.47 (2H, t, J = 7.5 Hz, CH2S), 2.23–2.10 (2H, m,
CH2CH2CF2CF3), 1.91–1.84 (2H, m, CH2CH2CF2CF3),
1.57–1.07 (17H, m, C3-CH3 and (CH2)7CH2S); MS (m/z)
561 (M+1).
5.45. (3RS,4RS)-7-Methoxymethyloxy-3-(4-methoxy-
methyloxyphenyl)-3-methyl-4-[10-(4,4,5,5,5-penta-
fluoropentylsulfanyl)decyl]chroman (21c) and (3RS,4SR)-
7-Methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-
methyl-4-[10-(4,4,5,5,5-pentafluoropentylsulfa-
nyl)decyl]chroman (22c)
These compounds, 21c (60%) and 22c (16%), were pre-
pared from 20c (3RS,4RS/3RS,4SR = 3:l) and 5a
using a procedure similar to those described for 11b
and 12b.
5.48. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-[10-
(4,4,5,5,5-pentafluoropentylsulfanyl)decyl]chroman-7-ol
(23c)
1H NMR (21c, 400 MHz, CDCl3) d: 7.13 (2H, d,
J = 9.2 Hz, ArH), 7.02 (2H, d, J = 9.2 Hz, ArH), 6.96–
6.94 (1H, m, ArH), 6.57–6.55 (2H, m, ArH), 5.18 (2H,
s, OCH2OCH3), 5.15 (2H, s, OCH2OCH3), 4.52 (1H,
d, J = 10.3 Hz, H-2), 4.26 (1H, d, J = 10.3 Hz, H-2),
3.50 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.65 (1H, br
s, H-4), 2.58 (2H, t, J = 7.0 Hz, CH2S), 2.49 (2H,
This compound was prepared from 21c using a proce-
dure similar to that described for 23b. 1H NMR
(400 MHz, CDCl3) d: 7.07 (2H, d, J = 8.8 Hz, ArH),
6.89 (1H, d, J = 8.1 Hz, ArH), 6.83 (2H, d,
J = 8.8 Hz, ArH), 6.39–6.35 (2H, m, ArH), 5.37 (1H,
br s, OH), 5.12 (1H, br s, OH), 4.51 (1H, d, J =
10.6 Hz, H-2), 4.23 (1H, d, J = 10.6 Hz, H-2), 2.60–
2.57 (3H, m, H-4 and CH2S), 2.49 (2H, t, J =
7.3 Hz, CH2S), 2.23–2.10 (2H, m, CH2CH2CF2CF3),
1.92–1.84 (2H, m, CH2CH2CF2CF3), 1.60–1.00
(21H, m, C3-CH3 and (CH2)9CH2S); MS (m/z) 589
(M+1).
t,
J = 7.5 Hz,
CH2S),
2.21–2.10
(2H,
m,
CH2CH2CF2CF3), 1.91–1.84 (2H, m, CH2CH2CF2CF3),
1.59–1.07 (21H, m, C3-CH3 and (CH2)9CH2S); MS
(m/z) 677 (M+1).
1H NMR (22c, 400 MHz, CDCl3) d: 7.29 (2H, d,
J = 8.8 Hz, ArH), 7.01 (1H, d, J = 8.4 Hz, ArH), 6.96
(2H, d, J = 8.8 Hz, ArH), 6.54–6.48 (2H, m, ArH),
5.14 (2H, s, OCH2OCH3), 5.11 (2H, s, OCH2OCH3),
4.22 (1H, d, J = 11.0 Hz, H-2), 3.93 (1H, d,
J = 11.0 Hz, H-2), 3.47 (3H, s, OCH3), 3.46 (3H, s,
OCH3), 3.04 (1H, br s, H-4), 2.59 (2H, t, J = 7.0 Hz,
CH2S), 2.50 (2H, t, J = 7.5 Hz, CH2S), 2.24–2.10 (2H,
5.49. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-[8-
(4,4,5,5,5-pentafluoropentylsulfinyl)octyl]chroman-7-ol
(24a)
This compound was prepared from 23a using a proce-
dure similar to that described for 14b. 1H NMR
(400 MHz, CDCl3 + D2O) d: 7.06 (2H, d, J = 8.8 Hz,
ArH), 6.91–6.85 (3H, m, ArH), 6.39–6.35 (2H, m,
ArH), 4.48 (1H, d, J = 10.6 Hz, H-2), 4.24 (1H, d,
J = 10.6 Hz, H-2), 2.87–2.55 (5H, m, H-4 and
CH2SOCH2), 2.34–2.19 (4H, m, CH2CH2CF2CF3),
1.72–0.88 (17H, m, C3-CH3 and (CH2)7CH2SO);
HRMS (ES-POS) calculated for C29H37F5O4S:
577.2411. Found: 577.2402 (ꢀ1.5 ppm).
m,
CH2CH2CF2CF3),
1.92–1.84
(2H,
m,
CH2CH2CF2CF3), 1.60–1.20 (21H, m, C3-CH3 and
(CH2)9CH2S); MS (m/z) 677 (M+1).
5.46. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-[9-
(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]chroman-7-ol
(23b)
A mixture of 21b (33 mg, 0.050 mmol) and a 10%
methanol solution of hydrogen chloride (1 mL) was
heated at 60 ꢂC for 15 min. Then, the reaction mixture
was concentrated and purified with column chroma-
tography (n-hexane/ethyl acetate = 2:1) to afford
27 mg (94%) of 23b. 1H NMR (400 MHz,CDCl3) d:
7.08 (2H, d, J = 8.8 Hz, ArH), 6.90 (1H, d,
J = 8.1 Hz, ArH), 6.83 (2H, d, J = 8.8 Hz, ArH),
6.39–6.35 (2H, m, ArH), 4.93 (1H, br s, OH), 4.73
(1H, br s, OH), 4.51 (1H, d, J = 10.4 Hz, H-2), 4.24
(1H, d, J = 10.4 Hz, H-2), 2.60–2.57 (3H, m, H-4
and CH2S), 2.49 (2H, t, J = 7.5 Hz, CH2S), 2.23–
2.10 (2H, m, CH2CH2CF2CF3), 1.92–1.84 (2H, m,
CH2CH2CF2CF3), 1.57–1.03 (19H, m, C3-CH3 and
(CH2)8CH2S); HRMS (ES-NEG) calculated for
C30H39F5O3S: 573.2462. Found: 573.2451 (ꢀ2.0 ppm).
5.50. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-[9-
(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman-7-ol
(24b)
This compound was prepared from 23b using a pro-
cedure similar to that described for 14b. 1H NMR
(400 MHz, CDCl3 + D2O) d: 7.07–7.05 (2H, m,
ArH), 6.89 (1H, d, J = 8.1 Hz, ArH), 6.84 (2H, d,
J = 8.4 Hz, ArH), 6.40–6.35 (2H, m, ArH), 4.50
(1H, d, J = 10.3 Hz, H-2), 4.24–4.20 (1H, m, H-2),
2.89–2.56 (5H, m, H-4 and CH2SOCH2), 2.31–2.18
(4H, m, CH2CH2CF2CF3), 1.80–1.03 (19H, m, C3-
CH3 and (CH2)8CH2SO); HRMS (ES-POS) calculated
for C30H39F5O4S: 591.2567. Found: 591.2566
(ꢀ0.3 ppm).

4818
Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
5.51. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-
[10-(4,4,5,5,5-pentafluoropentylsulfinyl)decyl]chroman-7-
ol (24c)
(+)-6 was first eluted at 9.6 min and (ꢀ)-6 was second elut-
ed at 11.2 min. Injection of 30 mg of 6 was repeated 109
times, and the total amounts of 1.03 g of (+)-6 and
1.10 g of (ꢀ)-6 were obtained. (+)-6 then crystallized
and X-ray analysis showed the absolute configuration to
be (R), which consequently indicated the other to be (S).
This compound was prepared from 23c using a procedure
similar to that described for 14b. H NMR (400 MHz,
1
CDCl3 + D2O) d: 7.05 (2H, d, J = 8.8 Hz, ArH), 6.89
(1H, d, J = 7.7 Hz, ArH), 6.84 (2H, d, J = 8.8 Hz, ArH),
6.39–6.36 (2H, m, ArH), 4.51 (1H, d, J = 10.3 Hz, H-2),
4.24 (1H, d, J = 10.3 Hz, H-2), 2.89–2.57 (5H, m, H-4
and CH2SOCH2), 2.33–2.16 (4H, m, CH2CH2CF2CF3),
1.84–1.02 (21H, m, C3-CH3 and (CH2)9CH2SO); HRMS
(ES-POS) calculated for C31H41F5O4S: 605.2724. Found:
605.2711 (ꢀ2.1 ppm).
(3R)-6: [a]D +327.4 (c 1.008, EtOH), 99.9% ee.
(3S)-6: [a]D ꢀ318.7 (c 0.996, EtOH), 98.7% ee.
1H NMR (400 MHz, CDCl3) of each enantiomer was
the same as that of 6.
5.55. (3R,4R)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thio-
chroman-7-ol ((3R,4R)-14b)
5.52. (3RS,4RS)-3-(4-Hydroxyphenyl)-3-methyl-4-[9-
(4,4,5,5,5-pentafluoropentylsulfonyl)nonyl]chroman-7-ol
(25b)
(3R,4R)-14b was prepared from (S)-6 using the same
procedure as that described for 14b. 1H NMR
(400 MHz, CDCl3) was the same as that of 14b; HRMS
(ES-POS) calculated for C30H39F5O3S2: 607.2339.
Found: 607.2325 (ꢀ2.3 ppm).
To a stirred mixture of 23b (64 mg, 0.11 mmol) and ox-
one (205 mg, 0.33 mmol) in tetrahydrofuran (2 mL)
was added water (1 mL) and stirred for 3 h at room
temperature. The reaction mixture was poured into
water and extracted with ethyl acetate. The extract
was dried over anhydrous magnesium sulfate, concen-
trated, and purified with column chromatography (n-
hexane/ethyl acetate = 1:1) to afford 64 mg (95%) of
25b. 1H NMR (400 MHz, CDCl3) d: 7.08 (2H, d,
J = 8.8 Hz, ArH), 6.90 (1H, d, J = 8.1 Hz, ArH), 6.84
(2H, d, J = 8.8 Hz, ArH), 6.39–6.35 (2H, m, ArH),
5.42 (1H, br s, OH), 4.85 (1H, br s, OH), 4.51 (1H,
d, J = 10.3 Hz, H-2), 4.24 (1H, d, J = 10.3 Hz, H-2),
3.07 (2H, t, J = 7.5 Hz, SO2CH2), 2.99 (2H, t,
J = 8.1 Hz, SO2CH2), 2.59 (1H, br s, H-4), 2.35–2.17
(4H, m, SO2CH2CH2CF2CF3), 1.84–1.06 (19H, m, ,
C3-CH3 and (CH2)8CH2SO2); HRMS (ES-NEG) calcu-
lated for C30H39F5O5S: 605.2360. Found: 605.2357
(ꢀ0.6 ppm).
5.56. (3S,4S)-3-(4-Hydroxyphenyl)-3-methyl-4-
[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thio-
chroman-7-ol ((3S,4S)-14b)
(3S,4S)-14b was prepared from (R)-6 using the same
procedure described for 14b. 1H NMR (400 MHz,
CDCl3) was the same as that of 14b; HRMS (ES-POS)
calculated for C30H39F5O3S2: 607.2339. Found:
607.2330 (ꢀ1.5 ppm).
5.57. Antiestrogenic activity
Antiestrogenic activity was determined as anti-utero-
trophic effect of the test compound in ICR mice. Mice
(6-weeks old) were ovariectomized (OVX) two weeks be-
fore the administration of the compounds. OVX mice
were treated with 0.1 lg of 17b-estradiol benzoate in pea-
nut oil solution subcutaneously along with the indicated
dose of the test compound in 10% EtOH-peanut oil solu-
tion subcutaneously or in 5% gum arabic-water suspen-
sion orally once a day for three consecutive days.
Approximately 24 h after the last administration, mice
were euthanized, and their uterine weights were mea-
sured. Antiestrogenic activity, determined by percent
inhibition of estradiol-stimulated uterine weight gain
from a compound, was calculated according to the fol-
lowing equation.
5.53. (3RS,4RS)-3-(4-Hydroxyphenyl)-4-[9-(4,4,5,5,5-
pentafluoropentylsulfinyl)nonyl]chroman-7-ol (26b)
Compound 26b was prepared with a procedure de-
scribed by this laboratory.19
1H NMR (270 MHz, CDCl3) d: 7.65–7.54 (1H, br s,
OH), 7.02–6.92 (3H, m, ArH), 6.80 (2H, d, J = 8.2 Hz,
ArH), 6.40 (1H, dd, J = 8.3 and 2.3 Hz, ArH),
6.36 (1H, d, J = 2.3 Hz, ArH), 5.59–5.52 (1H, br s,
OH), 4.43–4.32 (2H, m, C2-H), 3.38–3.24 (1H, m,
H-3), 2.95–2.58 (5H, m, CH2SOCH2 and H-4), 2.38–
2.10 (4H, m, SOCH2CH2CH2CF 2CF3), 1.82–0.90
(16H, m, (CH2)8CH2SO); HRMS (ES-POS) calculated
for C29H37F5O4S: 577.2411. Found: 577.2406
(ꢀ0.9 ppm).
% Inhibition = 100 · (1 ꢀ (T ꢀ C)/(E ꢀ C)), where T, E,
and C refer to uterine weight gain per body weight by
the test compound, by 17b-estradiol benzoate, and by
vehicle, respectively.
5.54. Chiral resolution of racemate 6
5.58. Estrogenic activity
The enantiomers, (R)-6 and (S)-6, were separated from
racemate 6 by CHIRALCELꢁ OD column using the
following conditions: column CHIRALCELꢁ OD
U2 · 25 cm; eluent hexane/isopropanol 70/30; flow rate
14.0 mL/min.
Estrogenic activity was determined as uterotrophic ef-
fect of the test compound in ICR mice. Mice (6-weeks
old) were ovariectomized (OVX) two weeks before the
administration of the test compound. OVX mice were

Y. Kanbe et al. / Bioorg. Med. Chem. 14 (2006) 4803–4819
4819
treated with the indicated dose of the test compound
References and notes
in 10% EtOH-peanut oil solution subcutaneously once
a day for three consecutive days. Approximately 24 h
after the last administration, mice were euthanized,
and their uterine weights were measured. Estrogenic
activity, determined by percent uterine weight gain
by the test compound, was calculated according to
the following equation.
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Acknowledgments
The authors thank Frances Ford and Dr. Paul Langman
of Chugai Pharmaceutical Co., Ltd. for their assistance
with English usage.
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