Synthesis and structure-activity relationship studies of 3-biaryl-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters

Article abstract of DOI:10.1016/j.bmc.2012.01.053

Stille cross coupling protocols were utilized for the synthesis of 3-(biaryl)-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl esters, which furnished products in high yields where in some cases Suzuki coupling under the conditions utilized provided complex reaction mixture. Samarium iodide reduction of the resulting coupling products produced both of the 2β-carbomethoxy-3- biaryl-8-oxabicyclo[3.2.1]octane diastereomers and the 2α-carbomethoxy-3- biaryl-8-oxabicyclo[3.2.1]octane diastereomers. Among the series synthesized, the benzothiophene substituted compounds demonstrated significant binding profiles of inhibition of WIN 35,438 with 177-fold selectivity for DAT versus SERT.

Full text of DOI:10.1016/j.bmc.2012.01.053

Bioorganic & Medicinal Chemistry 20 (2012) 2762–2772
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structure–activity relationship studies of 3-biaryl-8-oxabicy-
clo[3.2.1]octane-2-carboxylic acid methyl esters
Lokman Torun a, , Bertha K. Madras b, Peter C. Meltzer c,
⇑
⇑
a TUBITAK MAM Chemistry Institute P. K. 21 Gebze, Kocaeli 41470, Turkey
b Department of Psychiatry, Harvard Medical School and New England Regional Primate Center, Southborough, MA 01772, USA
c Organix Inc., 240 Salem Street, Woburn, MA 01801, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Stille cross coupling protocols were utilized for the synthesis of 3-(biaryl)-8-oxabicyclo[3.2.1]oct-2-ene-
2-carboxylic acid methyl esters, which furnished products in high yields where in some cases Suzuki
coupling under the conditions utilized provided complex reaction mixture. Samarium iodide reduction
of the resulting coupling products produced both of the 2b-carbomethoxy-3-biaryl-8-oxabicy-
Received 6 October 2011
Revised 26 January 2012
Accepted 30 January 2012
Available online 8 February 2012
clo[3.2.1]octane diastereomers and the 2a-carbomethoxy-3-biaryl-8-oxabicyclo[3.2.1]octane diastereo-
mers. Among the series synthesized, the benzothiophene substituted compounds demonstrated
significant binding profiles of inhibition of WIN 35,438 with 177-fold selectivity for DAT versus SERT.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Monoamine transporter ligands
Cocaine medications
Oxatropanes
Stille coupling
Suzuki coupling
1. Introduction
Cocaine’s addictive properties are thought to depend largely on
its ability to inhibit DAT.1,6–10 In addition to the DAT, cocaine also
Cocaine abuse is a serious international public health problem
that results from its powerful psychostimulant and reinforcing ef-
fects. Chronic use of cocaine can impair central nervous system
function by blockade of neurotransmitter uptake by dopamine,
serotonin and norepinephrine reuptake systems.1–5 Cocaine abuse
has profound effects on other organ systems, in particular the car-
diovascular system.
Considerable research has been devoted to gaining an under-
standing of the mechanism of action by which cocaine produces
its pharmacological effects. In the brain, the neurotransmitter
dopamine (DA) is released by presynaptic neurons into the synapse
for signal transduction, where it can then bind at dopamine recep-
tors of neighboring neurons. Under normal circumstances, excess
synaptic DA is recycled back into the presynaptic neurons by the
dopamine active transporter (DAT). Cocaine (1) binds to the DAT
and thus inhibits dopamine reuptake from the synapse, thereby
causing an accumulation of dopamine in the synapse. This, in turn,
leads to an increase in dopaminergic neurotransmission and con-
tinuous stimulation of receiving postsynaptic neurons.
binds at the serotonin reuptake transporter (SERT) and norepi-
nephrine (NET) transporters with moderate affinity.11–14
The DAT has been a prime focus for development of medications
for cocaine abuse and there have been intensive research efforts
over the last few decades toward discovery of cocaine pharmaco-
therapies based on this dopamine hypothesis1
The prototypical tropane (À)-2b-carbomethoxy-3b-(4-fluoro-
phenyl)tropane (WIN 35,428, compound 2), an analog of cocaine
(Fig. 1), has provided a lead for many researchers working in this
field.15 These analogs of WIN 35,428 have provided significant
insights and a large number of analogs have been reported to
O
CH3N8
O
CH3N
OCH3
OCH3
1
2
4
7
F
O
O
5
6
3
1
2
⇑
Corresponding authors. Tel.: +90 262 677 3400; fax: +90 262 641 2309 (L.T.);
fax: +1 781 932 4142 (P.C.M.).
Cocaine
WIN35,428
E-mail addresses: lokman.torun@mam.gov.tr (L. Torun), meltzer@organixinc.
com (P.C. Meltzer).
Figure 1. Structures of cocaine and WIN 35,428.
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2012.01.053

L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
2763
manifest selective and potent binding to monamine reuptake sys-
tems.16–20
biaryl substituents were directly connected to the tropane skeleton
through the heteroring of the side groups. We recently reported
the synthesis and DAT and SERT inhibitory potencies of a small ser-
ies of 3-biaryloxatropanes (Series I, in Fig. 2).32 We now report an
extension of this study to include remaining series (Fig. 2).
Syntheses of organostannane building blocks used to construct
the targeted compounds are presented in Scheme 1. Compounds
3a–d were prepared under Stille conditions in the presence of
Pd[P(Ph3)]4 in dioxane by the treatment of 3-bromo-1-iodoben-
zene with the corresponding arylstannanes and purified by column
chromatography. These compounds were then treated with n-BuLi
at À70 °C in THF and reacted with Bu3SnCl to furnish the interme-
diates 4a–d. Compound 4d was obtained along with 5 in approxi-
mately 1:1 ratio from the reaction of 3d as evidenced by the
presence of (M+H)+ peaks at 452 and 529 in the mass spectra of
the mixture, which correspond to the protonated molecular ion
peaks of 4d and 5, respectively. In addition the coupling between
compound 13 and mixture of 4d and 5 resulted in the formation
of the corresponding compounds 14i and 14j in 42% and 40%
yields, respectively, providing conclusive evidence for the ratio of
compounds 4d and 5. Purification of the organostannane interme-
diates 4a–d by chromatographic methods resulted in significant
destannylation. Therefore, they were used without purification
and in slight excess in the subsequent coupling reactions. Interme-
diate stannanes 7a–d could be purified by fractional distillation at
reduced pressure. Intermediates 10 and 12a–d were synthesized
similarly.
Synthesis of the target compounds was readily achieved by the
Stille cross-coupling protocol (Scheme 2). Thus reaction of triflate
1330 with the corresponding arylstannane intermediates in
Scheme 1 produced the desired products 14a–u in high yields.
Reactions were carried out in 1-methyl-2-pyrrolidinone at room
temperature in the presence of ZnCl2, tri-2-furylphosphine and
tris(dibenzylideneacetone)dipalladium(0) for overnight or in diox-
ane at reflux temperature in the presence of tetrakis(triphenyl-
phosphine)palladium(0) (Pd[(PPh3)]4) for overnight. The crude
reaction mixtures were treated with 10% aq KF to remove the tin
by-product by converting it into insoluble tributyltin fluoride. Fur-
ther purification was accomplished by flash chromatography on
silica gel with ethyl acetate/hexane (1:9) as the eluent. When nec-
essary, products were further purified by recrystallization. The
compounds were characterized by 1H NMR, mass spectrometry
and elemental analysis.
Despite extensive research on this subject,11,12 a comprehensive
understanding of the mechanism of action of cocaine and its tro-
pane analogs at the molecular level has been elusive. We21,22 have
reported that the 8-amine functionality present in WIN 35,428 is
not essential for inhibitory potency at the DAT. Indeed, this amine
can be exchanged for an ether,23 a thioether23 and even a methy-
lene24 with very limited effect on DAT or SERT inhibition.25 Da-
vies26 and Fu27 have reported the synthesis and binding profile of
3-heterobiaryl systems in the 8-azabicyclo[3.2.1]octane series
and shown a preferred selectivity of the SERT over the DAT for 4-
(2-pyrrolyl)phenyl10 and 4-(2-thiophenyl)phenyl17 at the 3-posi-
tion. In contrast 3-monoaryl systems demonstrated DAT
selectivity.28
We have reported that within the broad class of 8-heterobicy-
clo[3.2.1]octane systems, the 2b-carbomethoxy-3b-aryl configured
compounds showed interesting structure–activity relationship
(SAR) profiles.29–31 The chair configured diastereomers demon-
strated potency at DAT and SERT while the 2b-carbomethoxy-3a-
aryl ones manifested far weaker potency at SERT.
To further develop a comprehensive picture about the substitu-
ent role in the inhibition effect of DAT and SERT, the synthesis of
the ligands with the para- and meta-aryl phenyl groups and various
heteroaryl substituents at the 3-position of oxatropanes would be
important. In this regard, the present study undertook the synthe-
sis of several oxatropene series and evaluated SAR profiles of both
oxatropenes synthesized and some of their corresponding SmI2
reduction products. We now present synthesis and binding profiles
of Series of II–V.
2. Results and discussion
2.1. Chemistry
The primary goal of this study was to develop a broader under-
standing about the type and the nature of the side groups at the 3-
position of the oxatropane skeleton on the effect of inhibiting DAT
and SERT. The derivatives of the first series contained benzene
units with five-membered heteroaryl groups at the para-position.
The second series provided compounds with heteroaryl substitu-
ents at the meta-position of the benzene unit. Series III furnished
derivatives with heterobiarly substituents. In Series IV and V, the
The Stille cross-coupling reaction conditions were quite suc-
cessful in producing the target compounds (14e–u) in reasonably
high yields (67–93%) as seen in Table 1, comparable to the reported
reactions of Series I32 (14a–d). The exception was the reaction with
the benzoxazole stannane 7c intermediate for the synthesis of 14k
which was obtained in 10% yield.33
Compounds 14h and 14i were obtained nearly equal quantities.
The unintended compound 14i was the product from the coupling
with the intermediate 5. The reaction with indolestannane 10 pro-
duced the target compounds 14n with 56% yields as the major
product along with lactam 15 in 10% yields, which was conceivably
formed via intramolecular lactamization. Structures of the com-
pounds synthesized were confirmed by spectroscopic means and
spectral data are provided in Section 5.
We also utilized Suzuki conditions for the synthesis of some
oxatropenes. Under the Suzuki conditions employed (Pd(PPh3)4,
LiCl, Na2CO3, dioxane, reflux, 4h) the reaction between triflate 13
and benzofuranboronic acid provided compound 14j in 82% yield.
On the other hand, the reaction between compound 13 with
thiophenboronic acid furnished a complex reaction mixture. H
NMR spectrum of the crude reaction mixture showed three
well-resolved carbomethoxy signals with comparable intensities,
O
O
CO2Me
CO2Me
X
2
2
3
3
Y
O
X
II
I
Y
O
O
CO2Me
CO2Me
CO2Me
2
2
2
3
3
X
3
X
X
Y
Y
Y
III
IV
V
Series are designated on the basis of the 3-substituents
Compounds in each series are either 2,3-saturated
"ane" compounds or 2,3-unsaturated "ene" compounds
Figure 2. Structures of 8-oxa[3.2.1]octan(en)es.

2764
L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
Br
Bu3Sn
Br
SnBu3
S
X
X
Y
1) n-BuLi, THF, -70 °C, 2 h
2) Bu3SnCl
N
Y
3
a
b
c
Y = O
4
a
b
c
X = C Y = O
X = C Y = S
5
X = C
X = C
X = C
X = S
Y = S
Y = NMe
Y = N
X = C Y = NMe
X = S Y = N
d
d
X
Y
X
Y
1) n-BuLi, THF, -70
°
C, 2 h
SnBu3
2) Bu3SnCl
6
a
b
c
X = O
X = S
X = O
X = S
Y = C
Y = C
Y = N
Y = N
7
a
b
c
X = O Y = C
X = S Y = C
X = O Y = N
X = S Y = N
d
d
1) n-BuLi, THF -70 oC
1) n-BuLi, THF, -70
2) Bu2SnCl
°C
SnBu3
2) CO2 -70
°
C to rt
N
N
N
3) H2O
-
-
CO2 Li+
CO2 Li+
H
9
10
8
SnBu3
X
Y
X
Y
1) n-BuLi, THF, -70 °C, 2 h
2) Bu3SnCl
11
a
b
c
X = O
X = S
Y = C
Y = C
12
a
b
c
X = O
X = S
Y = C
Y = C
X = NMe Y = C
X = NMe Y = C
X = S
Y = N
X = S
Y = N
d
d
Scheme 1. Synthesis of organostannane intermediates.
O
O
indicating the presence of 14m (2,3-unsaturated) and two other
products, which are presumably 3,4-unsaturated compounds one
O
H1
H4β
O
O
O
ArSnBu3
Pd2dba3 ZnCl2
tri(2-furyl)phosphine
NMP, rt, 18 h.
with 2
a
-CO2CH3 and the other with 2b-CO2CH3 orientation.
,
,
Ar
OSO2CF3
Br
H4α
O
O
O
CO2Me
13
14
N
S
Scheme 2. Synthesis of 3-biaryloxatropenes via Stille coupling.
N
14i
15
due to the preferred b-face reduction. As previously reported, 2a-
COOCH3 diastereomers are generally not effective inhibitors of
DAT and SERT.6 Therefore our method of choice employed SmI2
in a protic solvent, which furnished 2b-carbomethoxy configured
compounds (Table 4) as the predominant reduction products.30,34
The 1H NMR spectral data for the bicyclic skeleton of
compounds 14e–u are in good agreement with the previous
assignments for the 2-carbomethoxy-3-(4-heteroaryl)-8-oxa-
[3.2.1]octene systems (14a–d). The chemical shifts of diagnostic
skeletal protons are given in Table 2. The H1 proton shows a dou-
blet between d 4.97–5.01 while H5 appears as multiplet at d 4.65–
4.68. In addition, H4b appears as a double doublet at d 2.98–3.09
This route produced the biologically more interesting 2b,3
a-con-
figured diastereomer (A, Fig. 3) in minor quantity.
Reduction of the bicyclo[3.2.1]octene systems with SmI2 in THF/
MeOH at À78 °C led to substrate dependent product distributions.
For example, biaryl groups attached to the bicyclooctene skeleton
with the H4 proton as a doublet at d 2.08–2.18.
through the phenyl ring, as in 14a–h, produced the 2b,3a (diaste-
a
The saturated target compounds (16a–u) were obtained by
reduction of the 2,3-ene precursors (14a–u). Catalytic reduction
provides mainly 2a-COOCH3 compounds (diastereomer C, Fig. 3)
reomer A) compounds 16a–d, 16g and 16h and the 2b,3b (diaste-
reomer B) compounds 16e, 16f and 16j as the two isolable
diastereomers, with the 2b,3b-chair conformer dominating (ca.

L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
2765
Table 1
The 3-biaryloxatropenes 13a–u
O
CO2Me
R
R
X
X
X
Z
X
Y
Y
Y
Y
X
Y
Yield (%)
X
Y
Yield (%)
X
Y
Yield (%)
X
Y
Z
Yield (%)
14a
b
c
O
S
NMe
S
C
C
C
N
82
85
79
79
14e
f
g
O
S
NMe
S
C
C
C
N
75
91
93
42
14j
k
l
m
n
O
O
S
S
C
N
N
C
C
81
10
67
78
56
14o
p
q
r
s
S
O
NMe
S
O
C
C
C
N
C
C
C
H
H
H
H
Ph
Ph
Ph
85
93
80
85
80
85
80
d
h
NH
t
u
S
NMe
Table 2
The trend of the diastereoselectivity is less clear and the prod-
Diagnostic 1H NMR data for compounds 14e–u
uct distribution is more complex with compounds 14j–u where
the heterocyclic ring is attached to the bicyclic skeleton. For exam-
ple, the diastereofacial selectivity was reversed in the case of thio-
Chemical shifts (ppm)
Compounds
H1
H4b(dd)
H4 (d)
H5
Compounds
a
furan 14o producing 2a3b (diastereomer D, 16t) as the major
O-2784
O-2550
O-2569
O-2755
O-2738
O-2551
O-2835
O-2695
O-2688
O-2856
O-2799
O-2785
O-2800
O-2786
O-2810
O-2811
O-2809
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
14o
14p
14q
14r
14s
14t
14u
5.03
4.94
5.02
4.97
4.97
4.86
4.87
4.94
4.95
5.02
4.92
4.83
5.08
4.81
4.87
4.93
5.11
2.98
3.05
2.99
3.08
3.09
3.04
3.15
3.13
3.08
3.25
3.03
2.95
2.90
3.02
2.99
3.04
2.95
2.16
2.25
2.15
2.26
2.22
2.30
2.49
2.43
2.26
2.53
2.23
2.23
2.14
2.33
2.25
2.24
2.21
4.65
4.68
4.64
4.68
4.68
4.71
4.76
4.74
4.68
4.64
4.65
4.66
4.61
4.64
4.69
4.65
4.64
product with 74% yield and 2b,3
a
(diastereomer A, 16u; 9% yield),
while the indole substituted compound 14n resulted in diastereo-
mers B, C and D (16o–q) in comparable yields (14%, 20% and 15%
yields, respectively). In contrast, the benzofuran derivative 14j,
produced diastereomer C, 16l, as the only isolable product in 60%
yield, while the benzothiofuran derivative 14m provided A and D
diastereomers, compounds 16m and 16n, with 48% and 6% yields,
respectively.
3. Discussion
There has been extensive research in the developing potential
medications for cocaine abuse. Much effort has been devoted for
synthesis and biological evaluation of cocaine-like compounds
where substituents at certain position were systematically
changed. In this regard 3b-aryl-8-azabicyclo[3.2.1]octane-2b-car-
boxylates are among the most widely studied oxatropanes. Intro-
duction of a naphthyl group into the tropane-based cocaine
analogs established much significant effect in SERT affinity. Davies
et al. showed that 2-naphthyl derivative at the 3b position resulted
in a very potent tropane analog.35 In addition, the 4-isopropyl phe-
nyl derivative demonstrated good selectivity for SERT trans-
porter.28 The N-methylated 3b-(4(2-pyrrolyl)phenyl derivative
showed 585-fold selectivity for SERT transporter over DAT
3:1 ratio). These two diastereomers (A and B) have the C2-carbo-
methoxyl group pointing toward the 8-oxygen of the bicyclic sys-
tem. The thiazole substituent on the 3-aryl ring had a significant
influence on the SmI2 reduction. For example, compound 14d
(4-thiazole: Series I) produced diastereomer A, compound 16d, in
9% yield as compared to compound 14h (3-thiazole) in Series II
provided diastereomer C, compound 16k in 23% yield as the only
isolable products.
O
O
O
O
OCH3
O
O
CO2Me
Ar
CO2Me
Ar
CO2Me
Ar
Ar
SmI2
THF:MeOH
-78
+
+
+
CO2Me
Ar
°
C
13
2β,3α
2β,3β
2α,3α
2α,3β
A
B
C
D
Boat
Chair
Boat
Chair
Figure 3. Synthesis of 3-(biaryl)-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters.

2766
L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
(1.05 nM vs 614 nM), respectively.26 On the other hand, the 3b-(5-
indlyl)-8-azabicyclo[3.2.1]octanes showed binding affinities to
both DAT and SERT transporters at 0.7–5.5 nM range with lack of
selectivity.26,41 In contrast, Dutta and co-workers showed that
replacement of the benzylic group by naphthyl moiety in structur-
ally constrained 1,4-diazabicyclo[3.3.1]nonane systems resulted in
reduction of the affinity for DAT.36 However, the 2-naphthyl deriv-
atives demonstrated about threefold more potency as compared to
the 1-naphthyl derivative.
Fu and co-workers reported binding profiles of series of tropane
analogs of cocaine. They saw that introduction of aryl or heteroaryl
groups in the para position of 3b-phenylazatropane ring provided
an increase in affinity and selectivity for SERT versus DAT and
NET transporters.37
From our laboratories, we reported high inhibition profile for
2b-carbomethoxy-3b-(2-naphthyl)-8-aza-bicyclo[3.2.1]octanes
(0.49 nM for DAT and 2.19 nM for SERT).21 In addition, we also ob-
served remarkable binding profiles of 2b-carbomethoxy-3b-(3,4-
dichlorophenyl)-8-aza-, 8-oxa-, and 8-thia-bicyclo[3.2.1]octanes,
which showed comparable nanomolar potency at DAT and SERT
(1.1, 3.3, 2.0 for DAT and 2.5, 4.7, 3.0 for SERT, respectively).25
A preliminary report32 from these laboratories described the
synthesis and DAT and SERT inhibitory potencies of compounds
in Series I (Scheme 2). We reported that within a series of
carboxylic acid methyl esters of (R,S)3-(4-heteroarylphenyl)-8-
oxabicyclo[3.2.1]octan(en)e, the saturated 3a-aryl and 3b-aryl dia-
stereomers were more potent inhibitors of the SERT compared
with their inhibition of the DAT. We have now extended the SAR
Table 3
2-Carbomethoxy-3-aryl-8-oxabicylclo[3.2.1]octenes, 17a–u: Inhibition of [3H]WIN 35,428a binding to the human dopamine transporter (hDAT) and [3H]citalopram bindingb to
the human serotonin transporter (hSERT)c
Series
Org#
Compd
X,Y
DAT
SERT
DAT/SERTc
IC50 (nM)
O-2546
O-2783
14a
14b
O,C
S
102
272
248
242
0.4
1
O
CO2Me
O-2547
O-2861
14c
14d
NCH3,C
S,N
>3
>3
l
l
M
M
>3
>3
l
l
M
M
1
1
X
Y
Series I
CO2Me
O-2784
O-2550
O-2569
O-2755
14e
14f
14g
14h
O,C
S,C
NCH3,C
S,N
>10
>10
l
M
710
>14
< 0.7
>14
1
O
X
lM
>1
l
M
Y
>3
>3
l
l
M
M
870
>3
l
M
Series II
Br
O
O
CO2Me
S
O-2738
14i
>3
l
M
>3
l
M
1
N
O-2551
O-2835
O-2695
O-2668
O-2856
14j
14k
14l
14m
14n
O,C
O,N
S,N
S,C
NH,C
349
>3
>3
>3
>2
>3
l
l
l
l
l
M
M
M
M
M
<0.1
1
<0.5
<0.004
<0.1
CO2Me
>3
>1
13
lM
lM
X
336
Y
Series III
CO2Me
O-2799
O-2785
O-2800
O-2768
14o
14p
14q
14r
S,C
O,C
NCH3,C
S,N
>3
>3
>3
>3
l
M
M
>3
>3
>3
>3
l
l
l
l
M
M
M
M
1
1
1
1
O
l
l
l
M
M
X
Y
Series IV
O-2810
O-2811
O-2809
14s
14t
14u
O
S
NCH3
>3
>3
>3
l
l
l
M
M
M
>3
>3
>3
l
l
l
M
M
M
1
1
1
O
CO2Me
X
Series V
O
O
O-2862
15
>3
lM
>3
lM
1
N
a
b
c
Binding affinity38 DAT: 12.9 nM; SERT: 160 nM.
Binding affinity DAT:39 17.7
l
m, SERT23: 2.43 nM.
Compounds are racemic. Each value is the mean of two or more independent experiments, each conducted in triplicate.

L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
2767
in this class by introduction of new aryl substituents at the
3-position of the 8-oxabicyclo[3.2.1]octane systems.
14k, benzothiazole 14l and indole 14n analogs have IC50 values
at the DAT of 349 nM, >3 M, >1 M and 336 nM, respectively,
l
l
In this study we synthesized new series of 2,3-ene compounds
14e–u, and 2,3-oxatropanes, compounds 16e–u, and investigated
their inhibitory potencies of DAT and SERT. Triflate 13 was reacted
under Stille conditions with arylstannanes in Scheme 1 to obtain
corresponding oxatropese 14e–u in high yields, which then were
subjected to SmI2 reduction conditions to obtain the 2,3-oxatro-
pane diastereomers 16e–u.
which showed the loss of selectivity and potency. The high binding
affinity of benzothiophene could be due to electronic or interaction
with distant binding location or both.
In the case of 2,3-‘ane’ compounds, although not selective, the
most potent tropane analogs are and found in Series III. In this ser-
ies, the benzothiophene substituted 2,3-saturated 2b3b-benzothio-
phene 16m demonstrated 9 nM and its 2a3b counterpart 16n
The data obtained for inhibition of ligand binding at both DAT
and SERT for the compounds in Tables 3 and 4 are striking. In
general, these compounds show very limited, if any, inhibitory
potencies. Thus, within these series of 2,3-unsaturated com-
pounds in Table 3, all the compounds are, at best, weak inhibi-
tors of the DAT, 14a (102 nM), 14b (248 nM), 14j (349 nm),
14n (336 nm) and SERT 14a (248 nm), 14b (242 nm). The
remaining compounds are effectively inactive at both transport-
showed 18 nM potencies at the DAT while they manifest IC50 val-
ues of 10 and 79 nM, respectively for SERT. It is noteworthy to
mention that the azatopane derivative of compound 16e as
reported by Tamagnan et al. demonstrated significantly higher
binding profile and SERT selectivity.37 2b-Carbomethoxy-3b-[2-
furylphenyl]-8-aza-bicyclo[3.2.1]tropane and its N-methylated
derivative showed 3.76 nM and 7.14 nM for DAT and 0.15 nm
and 1.13 nM for SERT, respectively. In contrast, compound 16e
showed 64 nM for DAT and 30 nM for SERT potencies.
ers (IC50 >1 lM). This is quite unlike the activity profiles we
previously reported for 8-oxatropanes devoid of a 3-biaryl or a
3-(5-membered ring) system.25 In that case, 2,3-ene-3-phenyl-
(or 3-naphthyl)-8-oxatropanes manifest substantial inhibition of
the DAT, as well as some considerable selectivity versus SERT
inhibition.
The exception was observed with benzothiophene substituted
compound 14m in Series III with 13 nm potency and significant
selectivity (<0.004) at the DAT. The benzufora 14j, benzoxazole
It is also clear that the influence of substituent bulk at the C3
position is important. A comparison of the IC50 values of the meta
substituted compounds 14e,f and 16g,h to the para substituted
counterparts 14a,b and 16a,b, respectively, shows that the exten-
sion site of the 5-membred heteroring, which increases bulkiness
of the ligand as in the case of meta substitution, resulted in the
significant loss of the binding ability to the DAT. Similar results
were also reported for oxatropene with 1-naphthyl (1720 nM),
Table 4
2a,b-Carbomethoxy-3a
,b-8-oxabicyclo[3.2.1]octanes 16a–u: Inhibition of [3H]WIN 35,428 binding to the human dopamine transporter (hDAT) and [3H]citalopram binding to the
human serotonin transporter (hSERT)a
Series
Org#
Compd
X,Y
Diastb,d (Scheme 3)
DAT
SERT
DAT/SERTc
IC50 (nM)
O-2504
O-2501
O-2570
O-2993
O-2502
O-2823
16a
16b
16c
16d
16e
16f
O,C
S,C
NCH3,C
S,N
O,C
NCH3,C
A: 2b, 3
A: 2b, 3
A: 2b, 3
A: 2b, 3
B: 2b, 3b
B: 2b, 3b
a
a
a
a
139
356
32
35
395
128
30
4
10
>2.5
>7
2
CO2Me
O
X
Y
2
>1
>1
64
>1
l
l
M
M
3
Series Id
l
M
566
>2
O-2608
O-2572
O-2573
O-3232
16g
16h
16j
O,C
S,C
NCH3,C
S,N
A: 2b, 3
A: 2b, 3
B: 2b, 3b
a
a
>1
>1
>1
>1
l
l
l
l
M
M
M
M
77
287
142
>1
>13
> 4
> 7
1
O
X
CO2Me
Y
2
16k
C: 2
a, 3b
lM
3
Series II
CO2Me
O-2607
O-3245
O-2758
O-2967
O-2969
O-2968
16l
16m
16n
16o
16p
16q
O,C
S,C
S,C
NH,C
NH,C
NH,C
C: 2
a
, 3
a
39
9
18
350
110
370
>1
10
79
>1
556
>1
l
l
M
<0.04
1
0.2
<0.3
0.2
0.4
O
2
A: 2b, 3b
D: 2 , 3b
C: 2 , 3
B: 2b, 3b
D: 2 , 3b
X
a
a
3
a
M
M
Y
Series III
CO2Me
a
l
O-2918
O-2917
16r
16s
S
O
C: 2
C: 2
a
, 3
a
a
487
>1
78
640
6
<2
O
a, 3
lM
2
X
3
Series IV
CO2Me
O-3230
O-3231
16t
16u
S
S
D: 2
A: 2b, 3
a
, 3b
a
>1
>1
l
M
M
>1
>1
l
M
1
1
O
2
l
lM
X
3
Series V
a
b
c
Each value is the mean of two or more independent experiments, each conducted in triplicate.
Compounds are racemic.
Ratio of SERT inhibition to DAT inhibition.
d
A–D refer to the diastereomers (Fig. 3).

2768
L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
2-naphthyl (20 nM), and 2-anthracenyl (>40,000 nM) substitution
at the C3 position. The least bulkier 2-naphthyl manifests substan-
tial DAT inhibitory potency.40 Accordingly, these results support
the notion that there is a significant steric barrier to binding if
the substituents lay transverse to the tropane skeleton as in the
compounds in Series II.
was washed with KF solution (10%, 20 mL) and brine (2 Â 30 mL).
The organic layer was dried over Na2SO4 and concentrated. At-
tempts to purify the crude materials by column chromatography
on deactivated silica or neutral alumina resulted in significant
decomposition of the stannanes. Therefore, the resulting crude
materials were used in the coupling reactions with the triflate
without further purification.
4. Conclusions
5.1.1. 2(3-Bromophenyl)furan (3a)
Colorless oil 80%. 1H NMR (CDCl3) 7.80–7.79 (m, 1H), 7.57–7.54
(dt, 1H), 7.45–7.44 (d, 1H), 7.34–7.33 (m, 1H), 7.23–7.18 (t, 1H),
6.64–6.63 (d, 1H), 6.46–6.45 (m, 1H). 13C NMR d 152.3, 142.6,
132.7, 130.2, 130.1, 126.6, 122.8, 122.2, 111.8, 106.0. Mass
(M+H)+ = 223/225.
In this report we utilized Stille protocols for the synthesis of
four novel series of oxabicyclo[3.2.1]octenes containing aryl sub-
stituents at the 3-position. SmI2 reduction of the Series II furnished
2b3
a and 2b3b diastereomers as the isolable products while the
remaining series produced complex product distributions. Analysis
of the inhibition data obtained for these compounds demonstrates
that the biaryl substitution at the 3-position of the bicyclooctene
14a–u did not have significant effect on the inhibition of WIN
35,438 nor the selectivity between DAT versus SERT. Compound
14m was striking in that it was a DAT inhibitor (IC50 = 13 nM)
5.1.2. 2(3-Bromophenyl)thiophen (3b)
Pale yellow oil 66%. 1H NMR (CDCl3 7.74–7.72 (m, 1H), 7.50–
7.47 (m, 1H), 7.39–7.35 (m, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.22–
7-16 (t, 1H), 7.06–7.03 (m 1H). Mass (M+H)+ = 239/241.
and quite selective (SERT IC50 = >3 lM, 177-fold), while its satu-
5.1.3. 2-(3-Bromophenyl)-1-meyhyl-1H-pyrrole (3c)
Colorless oil 58%. 1H NMR d7.55–7.54 (t, 1H), 7.42–7.38 (dt, 1H),
7.33–7.30 (dt, 1H), 7.26–7.20 (t, 1H), 7.71–7.69 (t, 1H), 6.24–6.22
(m, 1H), 6.19–6.17 (m, 1H), 3.64 (s, 3H). d 135,3, 132.9, 131.2,
129.8, 129.5, 126.9, 124.3, 122.4, 109.4, 107.9, 35.0. Mass
(M+H)+ = 236/238 (100%).
rated counterpart, 16m, was the most potent, but non-selective
DAT and SERT inhibitor (DAT IC50 = 9 nM; SERT IC50 = 10 nM) in
all series. The bicyclic aryl substituted oxatropenes, Series III in
general, and the corresponding reduction products have the stron-
gest interaction with the binding site of DAT as compared to the
remaining series.
It is important to note the fact that the relative positions of the
heteroatoms in 14j–l and less so 16l–q have such an impact on po-
tency and selectivity. In addition, compounds 14m and 16m are
more similar to our 3-naphthyl compounds21 in the earlier 8-hetero
series, in contrast to that compounds in Series I, II, IV and V look very
different that our earlier 3-aryl analogs.40 This difference could be
the subject of further studies including perhaps modeling studies.
5.1.4. 2-(3-Bromophenyl)thiazole (3d)
Colorless oil 57%. 1H NMR (CDCl3) d 8.13–8.12 (t, 1H), 7.86–7.85
(d, 1H), 7.83–7.82 (m, 1H), 7.53–7.49 (m, 1H), 7.33–7.32 (d, 1H),
7.29–7.24 (t, 1H). 13C NMR (CDCl3) d 166.4, 143.8, 135.3, 132.7,
130.3, 129.3, 125.0, 123.0, 119.9. Mass (M+H)+ = 240/242 (100%).
5.1.5. Tributyl-(3-furan-2-yl-phenyl)-stannane (4a)
Mass (M+H)+ = 435. The stannyl intermediate was used directly
in the following step without further purification.
5. Experimental section
All compounds are racemates (1R/1S). NMR spectra were re-
corded in CDCl3 on a JEOL 300 NMR spectrometer operating at
300.53 MHz for 1H and 75.58 MHz for 13C. TMS was used as inter-
nal standard. Melting points are uncorrected and were measured
on a Gallenkamp melting point apparatus. Thin-layer chromatog-
raphy (TLC) was carried out on Baker Si250F plates. Visualization
was accomplished with either UV exposure or treatment with
phosphomolybdic acid (PMA). Flash chromatography was carried
out on Baker silica gel 40 mm. Elemental analyses were performed
by Atlantic Microlab, Atlanta, GA. All reactions were conducted un-
der an inert (N2) atmosphere.
5.1.6. Tributyl-(3-thiophen-2-yl-phenyl)-stannane (4b)
Mass (M+H)+ = 451, The stannyl intermediate was used directly
in the following step without further purification.
5.1.7. 1-Methyl-2-(3-tributylstannyl-phenyl)-1H-pyrrole (4c)
Mass (M+H)+ = 448. The stannyl intermediate was used directly
in the following step without further purification.
5.1.8. 2-(3-Tributylstannanyl-phenyl)-thiazole (4d) and 2-(3-
tributylstannanyl-phenyl)-5-bromo-thiazole (5)
Brown oil (M+H)+ = 529/531, (M+H)+ = 449/451. The stannyl
intermediates were used directly in the following step without fur-
ther purification.
5.1. General procedure for organostannane building blocks
A mixture of 1-bromo-3-iodobenzene (25 mmol), 1.0 equiv of
arylstannanes and 0.05 equiv of Pd(PPh3)4 was refluxed under
nitrogen for 5 h in dioxane (100 mL) (Scheme 1). After cooling
and evaporation of the volatiles, the residue was dissolved in EtOAc
(100 mL). KF solution (10%, 50 mL) was added and the solution was
stirred at room temperature for 30 min. The resultant precipitate
was removed by suction filtration. The organic layer was washed
with water (3 Â 50 mL), dried over Na2SO4 and concentrated. The
product was purified by flash column chromatography (eluent:
hexane)
5.1.9. Benzofuran-2-yl-tributylstannane (7a)
Pale yellow oil 90%, bp 164 °C at 0.13 mm Hg. 1H NMR (CDCl3) d
7.56–7.48 (m, 2H), 7.22–7.16 (m, 2H), 6.90–6.89 (m, 1H), 1.65–1.54
(m, 6H), 1.39–1.29 (m, 6H), 1.27–1.12 (m, 6H), m 0.92–0.87 (m,
9H). 13C NMR (CDCl3) 165.34, 158.62, 128.03, 123.29, 121.98,
120.22, 117.99, 110.94, 28.95, 27.19, 13.65, 10.14. Mass spectrum
did not have (M+H)+ peak at m/z = 408. A common fragment ion
at m/z = 291 for (C12H27Sn)+ was present (100%). Anal. (C20H32OSn)
C, H.
The resulting biarylbromides 2a–d (5 mmol) were treated in
THF (25 mL) with n-BuLi (1.05 equiv, 2.5 M in THF) at À70 °C for
1 h followed by addition of tributyltin chloride (1.0 equiv) via syr-
inge. The reaction was allowed to warm to room temperature with
stirring over 30 min. Hexane (50 mL) was added and the solution
5.1.10. Benzo[b]thiophen-2-yl-tributylstannane (7b)
Pale yellow oil 67.4%, bp 174 °C at 0.13 mm Hg. 1H NMR (CDCl3) d
7.90–7.87 (m, 1H), 7.82–7.80 (m, 1H), 7.42–7.23 (m, 3H), 1.69–1.50
(m, 6H), 1.42–1.30 (m, 6H), 1.27–1.05 (m, 6H), m 0.93–0.88 (m, 9H).
13C NMR (CDCl3) 144.31, 141.03, 139.74, 132.03, 123.66, 123.27,

L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
2769
122.68, 121.79, 28.97, 27.27, 13.67, 10.75. Mass spectrum did not
have (M+H)+ peak at m/z = 424. A common fragment ion at m/
z = 291 (C12H27Sn)+ was present (100%). Anal. (C20H32SSn) C, H.
(0.6 g, 10 mol %) were refluxed under nitrogen in dioxane
(100 mL) for overnight. Ethyl acetate (150 mL) and 10% aqueous
KF (100 mL) were added and stirring was continued for 20 min.
Precipitate formed was filtered off and the filtrate was washed
with water (3 Â 500 mL), dried over Na2SO4 and concentrated in
vacuo. Further purification was done on silica gel column using
EtOAc/Hexanes (1:9) as the eluent. Hexanes (1:9) as the eluent.
5.1.11. 2-Tributylstannyl-benzooxazole (7c)
Pale yellow oil 49%, bp >140 °C at 0.13 mm Hg. 1H NMR (CDCl3)
d 7.79–7.75 (m, 1H), 7.57–7.54 (m, 1H), 7.32–7.26 (m, 2H), 1.68–
1.57 (m, 6H), 1.42, 1.20 (m, 12H), 0.92–0.87 (t, 9H) 13C NMR
(CDCl3) 175.92, 152.01, 141.34, 124.32, 123.43, 119.64, 110.28,
28.76, 27.11, 13.60, 10.74. Mass (M+H)+ = 410 (100%).
5.1.19.2. Method II.
Triflate 13 (1.75 g, 5.5 mmol), arylstann-
ane (1.2 equiv), ZnCl2 (11.0 mmol), tri-2-furylphosphine (0.25 g,
1.1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.5 g,
0.5 mmol) were stirred in 1-methyl-2-pyrrolidinone (100 mL) at
room temperature for overnight under nitrogen. Ethyl acetate
(150 mL) and 10% aqueous KF (100 mL) were added and stirring
was continued for 20 min. Precipitate formed was filtered off and
the filtrate was washed with water (3 Â 500 mL), dried over
Na2SO4 and concentrated in vacuo. Further purification was done
on silica gel column using EtOAc/Hexanes (1:9) as the eluent. Hex-
anes (1:9) as the eluent.
5.1.12. 2-Tributylstannyl-benzothoazole (7d)
Pale yellow oil 84%, bp 165 °C at 0.13 mm Hg. 1H NMR (CDCl3) d
8.18–8.16 (m, 1H), 7.97–7.94 (m, 1H), 7.46–7.43 (m, 1H), 7.39–7.33
(m, 1H), 1.67–1.58 (m, 6H), 1.40–1.23 (m, 12H), 0.94–0.86 (m, 9H).
13C NMR (CDCl3) 177.66, 156.06, 136.25, 125.26, 124.35, 122.76,
121.28, 28.82, 27.20, 13.61, 11.23. Mass: (M+H)+ = 426 (100%).
Anal. (C19H31NSSn) C, H.
5.1.13. Synthesis of tributylstannanylindol-1-carboxylic acid
lithium salt (10)
5.1.20. Spectral data
n-Butyllithium (2.5 M, 36 mL) was added to indole solution
(10.0 g, 85.5 mmol) in THF (170 mL) under nitrogen at À70 °C.
After stirring for 30 min, excess of dry ice was added and stirring
was continued at that temperature for 1 h and then allowed to
warm to room temperature. Volatiles were removed to dryness
and 21.5 g of white/gray solid was obtained. The solid was then
dissolved in 200 mL of anhydrous THF and cooled to À70 °C. n-BuLi
(36 mL, 2.5 M), was added and mixture was stirred for 2 h. Bu3SnCl
(23.2 mL) was added via syringe and mixture was allowed to warm
to room temperature. Ethyl acetate (150 mL) were added and mix-
tures was washed with brine (100 mL) and water (2 Â 50 mL),
dried over Na2SO4 and concentrated. The reddish oil (44.8 g) was
used in the next step.
5.1.20.1. (R,S) 3-(3-Furan-2-yl-phenyl)-8-oxa-bicyclo[3.2.1]oct-
2-ene-2-carboxylic acid methyl ester (14e).
White solid 75%
yield, mp 81–81 °C. 1H NMR (CDCl3) d 7.60–7.57 (m, 1H), 7.45–7.43
(m, 2H), 7.36–7.31 (t, 1H), 7.02–6.99 (m, 1H), 6.64–6.63 (d, 1H),
6.47–6.46 (m, 1H). 5.03–5.02 (d, 1H), 4.67–4.63 (m, 1H), 3.49 (s,
3H), 3.02–2.94 (dd, 1H), 2.22–2.13 (m, 4H), 1.84–1.78 (m, 1H).
13C NMR (CDCl3) d 166.4, 153.6, 144.6, 142.0, 141.4, 130.6, 128.3,
125.7, 122.9, 122.0, 11.7, 105.2, 73.4, 73.1, 51.3, 41.5, 35.6, 29.8.
Mass (M+H)+ = 311 (60%), (MÀOCH3)+ = 279 (100%). Anal.
(C19H18O4) C, H.
5.1.20.2. (R,S) 3-(3-Thiophen-2-yl-phenyl)-8-oxa-bicyclo[3.2.1]
oct-2-ene-2-carboxylic acid methyl ester (14f).
Pale yellow
solid 91% yield, mp 93–94 °C. 1H NMR (CDCl3) d 7.59–7.56 (m,
2H), 7.39–7.35 (m, 2H), 7.35–7.24 (m, 1H), 7.20–7.18 (d, 1H),
7.01–7.00 (m, 1H), 4.95–4.93 (d, 1H), 4.69–4.67 (m, 1H), 3.71 (s,
3H), 3.09–3.02 (dd, 1H), 2.29–2.05 (m, 4H), 1,84–1.72 (m, 1H).
13C NMR (CDCl3) d 167.5, 144.8, 140.5, 133.9, 133.1, 132.0, 128.9,
127.7, 127.4, 125.7, 122.8, 74.00, 73.1, 51.8, 40.5, 35.2, 29.6. Mass
(M+H)+ = 327 (100%), (MÀOCH3)+ = 295 (15 %). Anal. (C19H18O3S)
C, H.
5.1.14. 2-Phenylfuran (11a)
Pale yellow oil 79%. 1H NMR (CDCl3) d 7.70–7.66 (m, 2H), 7.47–
7.46 (m, 1H), 7.41–7.35 (m, 2H), 7.28–7.23 (m, 1H), 6.65–6.64 (d,
1H), 6.43–6.46 (m, 1H). 13C NMR (CDCl3) d 153.9, 141.9, 130.8,
128.2, 127.3, 123.7, 111.6, 104.9.
5.1.15. 2-Phenylthiophen (11b)
White solid 84% yield, mp 33–34 °C. 1H NMR (CDCl3) d 7.63–
7.60 (m, 2H), 7.41–7.35 (m, 2H), 7.32–7.25 (m, 3H), 7.09–7.07
(m, 1H). 13C NMR (CDCl3) d 144.3, 134.3, 128.8, 127.9, 127.4,
125.8, 124.7, 123.
5.1.20.3. (R,S) 3-[3-(1-Methyl-1H-pyrrol-2-yl)-phenyl]-8-oxa-bicy-
clo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (14g).
Pale
yellow oil 93% yield. 1H NMR (CDCl3) d 7.37–7.29 (m, 2H), 7.14–7.13
(m, 1H), 7.06–7.02 (dt, 1H), 6.71–6.70 (t, 1H), 6.22–6.16(m, 2H), 5.04–
5.00 (d, 1H), 4.67–4.62 (m, 1H), 3.64 (s, 3H), 3.51 (s, 3H), 3.03–2.95
(dd, 1H), 2.26–2.04 (m, 4H), 1.83–1.73 (m, 1H). 13C NMR (CDCl3) d
166.3, 144.8, 141.0, 134.2, 133.0, 131.7, 128.0, 127.7, 127.0, 125.0,
123.7, 108.6, 107.7, 73.4, 73.1, 51.3, 41.7, 35.6, 35.0, 29.8. Mass
(M+H)+ = 324 (100%). Anal. (C20H21NO3) C, H, N.
5.1.16. 1-Methyl-2-phenylpyrrole (11c)
Colorless oil 78%. 1H NMR (CDCl3) d 7.39–7.33 (m, 4H), 7.31–
7.25 (m, 1H), 6.69–6.68 (m, 1H), 6.24–6.17 (m, 2H), 3.63 (s, 3H).
Mass (M+H)+ = 158 (100%).
5.1.17. Tributyl-(5phenyl-furan-2-yl)-stannane (12a)
1H NMR (CDCl3) d 7.69–7.66 (m, 2H), 7.39–7.34 (m, 2H), 7.24–
7.19 (m, 1H), 6.68–6.67 (dt, 1H), 6.22–6.21 (d, 1H), 1.66–1.55 (m,
6H), 1.42–1.30 (m, 6H), 1.14–1.09 (m, 6H), 0.94–0.88 (t, 9H). 13C
NMR CDCl3) d 160.9, 158.4, 131.4, 131.4, 128.6, 123.7, 123.4,
204.9, 28.9, 27.2, 13.7, 10.2.
5.1.20.4. (R,S) 3-(3-Thiazol-2-yl-phenyl)-8-oxa-bicyclo[3.2.1]oct-
2-ene-2-carboxylic acid methyl ester (14h).
Pale yellow 42%
yield, mp 92–94 °C. 1H NMR (CDCl3) d 7.94–7.91 (m, 2H), 7.75 (s,
1H), 7.45–7.40 (m, 3H), 4.98–4.96 (d, 1H), 4.69–4.67 (m, 1H),
3.72 (s, 3H), 3.12–3.04 (dd, 1H), 2.28–2.04 (m, 4H), 1.80–1.78 (m,
1H). 13C NMR (CDCl3) d 168.4, 166.6, 142.5, 135.6, 133.6, 133.3,
130.9, 129.2, 128.9, 126.4, 73.8, 72.9, 51.9, 40.8, 35.1, 29.6. Mass
(M+H)+ = 328 (100%). Anal. (C18H17NO3S) C, H, N.
5.1.18. 1-Methyl-2-phenyl-5-tributylstannanyl-1H-pyrrole (12c)
(M+H)+ = 448.
5.1.19. General synthesis of (R/S), 3-aryl-8-oxabicyclo[3.2.1]oct-
5.1.20.5. (R,S)-3-[2-(3-Bromophenyl)-thiazol-5-yl]-8-oxa-bicyclo
2-ene-2-carboxylic acid methyl esters
[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (14i).
Pale
5.1.19.1. Method I.
Triflate 13 (1.75 g, 5.5 mmol), arylstann-
yellow solid 40% yield, mp 92–94 °C. 1H NMR (CDCl3) d 8.11–8.10 (t,
ane (1.2 equiv) and tetrakis(triphenylphosphine)palladium(0)
1H), 7.85–7.82 (m, 1H), 7.76 (s, 1H), 7.56–7.52 (m, 1H), 7.33–7.27 (t,

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L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
1H), 4.98–4.96 (d, 1H), 4.70–4.66 (m, 1H), 3.73 (s, 3H), 3.12–3.05 (dd,
1H), 2.28–2.05 (m, 4H), 1.79–1.72 (m, 1H). 13C NMR (CDCl3) d 166.4,
142.7, 136.3, 135.2, 134.0, 132.9, 130.9, 130.4, 129.2, 125.0, 123.1,
73.8, 72.9, 51.9, 40.9, 35.2, 29.6. Mass (M+H)+ = 406/408 (100%). Anal.
(C18H16BrNO3S) C, H, N.
5.1.20.12. (R,S) 3-Furan-2-yl-8-oxa-bicyclo[3.2.1]oct-2-ene-2-
carboxylic acid methyl ester (14p). Method I, yellow solid
93% yield, mp 56–57 °C. 1H NMR (CDCl3) d 7.37–7.36 (d, 1H),
7.52–7.52 (d, 1H), 6.40–6.38 (m, 1H), 4.84–4.82 (d, 1H), 4.68–
4.64 (m, 1H), 3.77 (s, 3H), 2.99–2.91 (dd, 1H), 2.26–2.02 (m, 4H),
1.78–1.72 (m, 1H) 13C NMR (CDCl3) d 168, 151.4, 142.5, 130.1,
111.1, 109.8, 73.7, 72.7, 51.6, 35.4, 35.3, 29.3. Mass (M+H)+ = 235
(100%) (MÀOCH3)+ = 203 (80%). Anal. (C13H14O4) C, H.
5.1.20.6. Synthesis of (RS), 3-Benzofuran-2-yl-8-oxa-bicyclo[3.2.1]
oct-2-ene-2–carboxylic acid methyl ester (14j).
White solid
81% yield, mp 95–96 °C. 1H NMR (CDCl3) d 7.55–7.52 (m, 1H), 7.40–
7.37 (m, 1H), 7.30–7.25 (dt, 1H), 7.22–7.17 (dt, 1H), 6.74–6.71 (d,
1H), 4.87–4.85 (d, 1H), 4.74–4.69 (m, 1H), 3.81 (S, 3H), 3.08–3.01
(dd, 1H), 2.32–2.09 (m, 4H), 1.82–1.77 (m, 1H). 13C NMR (CDCl3) d
168.4, 154.6, 153.3, 135.6, 133.1, 128.1, 125.0, 122.9, 121.3, 110.9,
105.6, 74.0, 72.9, 52.0, 35.4, 35.1, 29.4. Mass. (M+H)+ = 285 (70%),
(MÀOCH3)+ = 253 (100%). Anal. (C17H16O4) C, H.
5.1.20.13. (R,S) 3-(1-Methyl-1H-pyrrol-2-yl-8-oxa-bicyclo[3.2.1]
oct-2-ene-2-carboxylicacidmethylester(14q).
MethodI,pale
yellow oil 80% yield. 1H NMR (CDCl3) d 6.65–6.63 (M, 1H), 6.15–6.13
(M, 1H), 6.01–5.99(M, 1H), 5.09–5.07(M, 1H), 4.63–4.59 (M, 1H), 3.62
(S, 3H), 3.41 (S, 3H), 2.94–2.86 (DD, 1H), 2.20–2.06 (M, 4H), 1.79–1.69
(M, 1H). 13C NMR (CDCl3) d 165.5, 137.2, 133.4, 131.9, 107.8, 107.7,
73.4, 73, 71.7, 42.4, 33.9, 29.6. Mass (M+H)+ = 248 (100%)
(MÀOCH3)+ = 216 (30%). Anal. C14H17NO3) C, H, N.
5.1.20.7. Synthesis of (RS), 3-Benzoxazol-2-yl-8-oxa-bicyclo[3.2.1]
oct-2-ene-2–carboxylic acid methyl ester (14k).
Pale yellow
solid 10% yield, mp 85–86 °C. 1H NMR (CDCl3) d 7.75–7.70 (m, 1H),
7.50–7.45 (m, 1H), 7.38–7.31 (m, 2H), 4.88–4.86 (d, 1H), 4.79–4.74
(m, 1H), 3.81 (s, 3H), 3.19–3.11 (dd, 1H), 2.53–2.47 (d, 1H), 2.32–
2.20 (m, 2H), 2.18–2.10 (m, 1H), 1.86–1.82 (m, 1H). 13C NMR (CDCl3)
d. 167.4, 160.9, 150.3, 141.3, 141.1, 125.6, 124.6, 123.2, 120.3, 110.5,
73.9, 73.0, 52.4, 35.2, 29.5. Mass. (M+H)+ = 286 (100%). Anal.
(C16H15NO4) C, H, N.
5.1.20.14. (R,S) 3-Thiazol-2-yl-8-oxa-bicyclo[3.2.1]oct-2-ene-2-
carboxylic acid methyl ester (14r).
Method I, yellow oil 85%
yield. 1H NMR (CDCl3) 7.81–7.80 (d, 1H), 7.35–7.34 (d, 1H), 4.89–
4.87 (d, 1H), 4.74–4.70 (m, 1H), 3.72 (s, 3H), 3.13–3.05 (dd, 1H),
2.44–2.38 (d, 1H), 2.29–2.17 (m, 2H), 2.15–2.07 (m, 1H), 1.88–1.74
(m, 1H). 13C NMR (CDCl3) 167.43, 165.1, 142.9, 135.9, 130.9, 119.7,
73.7, 73.1, 52, 38.1, 35.1, 29.5. Mass (M+H)+ = 252 (100%)
(MÀOCH3)+ = 220 (20%). Anal. (C12H13NO3S) C, H, S, N.
5.1.20.8. (R,S) 3-Thiazole-2-yl-8-oxa-bicyclo[3.2.1]oct-2-ene-2-
carboxylic acid methyl ester (14l).
Method II, colorless oil
5.1.20.15. (R,S) 3-(5-Phenyl-furan-2-yl)-8-oxa-bicyclo[3.2.1]oct-
67% yield. 1H NMR (CDCl3) d 8.03–8.00 (m, 1H), 7.89–7.86 (m,
1H), 7.55–7.45 (m, 1H), 7.42–7.36 (m, 1H), 4.95–4.93 (d, 1H),
4.76–4.72 (m, 1H), 3.70 (s, 3H), 3.17–3.09 (dd, 1H), 2.47–2.41 (d,
1H), 2.31–2.11 (m, 3H), 1.92–1.83 (m, 1H). 13C NMR (CDCl3) d
166.8, 165.7, 153.1, 137.7, 135.2, 132.4, 126.2, 125.4, 123.4,
121.5, 73.7, 73.1, 52.1, 38.4, 35.2, 29.7. Mass. (M+H)+ = 302
(100%), (MÀOCH3)+ = 270 (10%).
2-ene-2-carboxylic acid methyl ester (14s).
Method I, white
solid 80% yield, mp 85–87 °C. 1H NMR (CDCl3) d 7.62–7.60 (m, 2H),
7.40–7.35 (m, 2H), 7.28–7.26 (m, 1H), 6.67–6.65 (d, 1H), 6.61–6.58
(d, 1H), 4.87–4.86 (d, 1H), 4.71–4.67 (m, 1H), 3.77 (s, 3H), 3.05–
3.98 (dd, 1H), 2.30–2.04 (m, 4H), 1.82–1.67 (m, 1H). 13C NMR
(CDCl3) d 169, 154, 150, 130.3, 130, 129, 128, 125, 124, 112, 107,
74, 73, 52, 35, 30. Mass (M+H)+ = 310 (100%) (MÀOCH3)+ = 279
(30%). Anal. (C19H18O4) C, H.
5.1.20.9. (R,S)-3-[2-Benzothiophen-2-yl]-8-oxa-bicyclo[3.2.1]oct-
2-ene-2carboxylic acid methyl ester (14m).
White solid 78%
5.1.20.16. (R,S) 3-(5-Phenyl-thiophrn-2-yl)-8-oxa-bicyclo[3.2.1]
yield, mp 84–86 °C. 1H NMR (CDCl3) d 7.79–7.76 (m, 1H), 7.74–7.71
(m, 1H), 7.37–7.30 (m, 2H), 7.18 (s, 1H), 4.96–4.94 (d, 1H), 4.70–
4.66 (m, 1H), 3.65 (s, 3H), 3.11–3.04 (dd, 1H), 2.30–2.20 (m, 4H),
1.85–1.76 (m, 1H). 13C NMR (CDCl3) d 167.1, 141.6, 139.7, 139.4,
134.2, 133.8, 124.6, 124.4, 123.7, 122.4, 122.1, 73.9, 73.1, 51.9, 40.8,
35.3, 29.7. Mass. (M+H)+ = 301 (60%), (MÀOCH3)+ = 269 (100%). Anal.
(C17H16O3S) C, H.
oct-2-ene-2-carboxylic acid methyl ester (14t).
Method I, yel-
low solid 85% yield, mp 92–93 °C. 1H NMR (CDCl3) d 7.58–7.55 (m,
2H), 7.39–7.33 (m, 2H), 7.30–7.24 (m, 1H), 7.19–7.18 (d, 1H), 7.00–
6.99 (d, 1H), 4.94–4.92 (d,1H), 4.68–4.63 (m, 2H), 3.70 (s, 3H), 3.08–
3.01 (dd, 1H), 2.28–2.13 (m, 4H), 1.79–1.75 (m, 1H). 13C NMR (CDCl3)
d 167.5, 144.8, 133.9, 133, 128.8, 127.7, 125.7, 122.8, 73.9, 73.1, 51.8,
40.4, 35.1, 29.6. Mass (M+H)+ = 327 (100%) (MÀOCH3)+ = 295 (20%).
Anal. (C19H18O3S) C, H, S.
5.1.20.10. (RS), 3-(1H-Indol-2-yl)-8-oxa-bicyclo[3.2.1]oct-2-ene-
2–carboxylic acid methyl ester (14n).
Method II, light yellow
5.1.20.17. (R,S) 3-(1-Methyl-1H-pyrrol-4-phenyl)-2-yl-8-oxa-
solid 56% yield, mp 132–134 °C. 1H NMR (CDCl3) d 7.59–7.56 (d,
1H), 7.41–7.38 (m, 1H), 7.23–7.18 (m, 1H), 7.09–7.03 (m, 1H),
6.74–6.73 (m, 1H), 5.03–5.01 (m, 1H), 4.66–4.62 (m, 1H), 3.79 (s,
3H), 3.28–3.21 (dd, 1H), 2.56–2.50 (d, 1H), 2.16–2.07 (m, 3H),
1.69–1.62 (m, 1H). 13C NMR (CDCl3) d 168.3, 136.4, 135.3, 127.2,
127.1, 123.7, 120.8, 119.8, 111.6, 105.6, 73.9, 72.8, 52.2, 37.9,
35.4, 29.3. Mass. (M+H)+ = 284 (100%). Anal. (C17H17NO4) C, H, N.
bicyclo[3.2.1]oct-2-ene-2-carboxylic
(14u).
Acid
Methyl
Ester
Method I, pale yellow oil 80% yield. 1H NMR (CDCl3) d
6.65–6.63 (M, 1H), 6.15–6.13 (M, 1H), 6.01–5.99 (M, 1H), 5.09–
5.07 (M, 1H), 4.63–4.59 (M, 1H), 3.62 (S, 3H), 3.41 (S, 3H), 2.94–
2.86 (DD, 1H), 2.20–2.06 (M, 4H), 1.79–1.69 (M, 1H). 13C NMR
(CDCl3) d 165.5, 137.2, 133.4, 131.9, 107.8, 107.7, 73.4, 73, 71.7,
42.4, 33.9, 29.6. Mass (M+H)+ = 248 (100%) (MÀOCH3)+ = 216
(30%). Anal. (C14H17NO3) C, H, N.
5.1.20.11. (R,S) 3-Thiophen-2-yl-8-oxa-bicyclo[3.2.1]oct-2-ene-
2-carboxylic acid methyl ester (14o).
Method I, yellow solid
5.1.20.18. Compound 15.
Yellow solid 10% yield, mp 171–
85% yield. 1H NMR (CDCl3) d 7.29–7.26 (m, 1H), 7.01–7.98 (m, 2H),
4.92–4.91 (d, 1H), 4.67–4.63 (m, 1H), 3.67 (s, 3H), 3.07–2.99 (dd,
1H), 2.25–2.04 (m, 4H), 1.81–1.72 (m, 1H). 13C NMR (CDCl3) d
167.4, 1412.3, 133.3, 132.3, 126.8, 126.1, 125.8, 73.8, 73.1, 51.7,
40.8, 35.1, 29.6. Mass (M+H)+ = 251 (50%) (MÀOCH3)+ = 219
(100%). Anal. (C13H14O3S) C, H, S.
172 °C. 1H NMR (CDCl3) d 7.64–7.61 (m, 1H), 7.36–7.33 (d, 1H),
7.26–7.20 (dt, 1H), 7.07–7.01 (dt, 1H), 6.28 (s, 1H), 4.94–4.92 (m,
1H), 4.78–4.73 (m, 1H), 3.03–2.95 (dd, 1H), 2.31–2.08 (m, 4H),
1.77–1.70 (m, 1H). 13C NMR (CDCl3) d 162.5, 140.7, 140.6, 138.6,
134.4, 133.5, 127.3, 122.8, 122.6, 112.0, 105.8, 72.3, 70.3, 35.6,
31.9, 29.8. Mass. (M+H)+ = 252 (100%). Anal. (C16H13NO2) C, H, N.

L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
2771
5.2. General procedure for SmI2 reduction
54.1, 53.9, 50.0, 39.6, 39.4, 30.0, 29.6, 28.4, 25.7. Mass
(M+H)+ = 330. Anal. (C18H19NO3S) C, H, N, S.
Compounds 14 (2–5 mmol) were dissolved in THF/MeOH or
THF:2-propanol (9:1, 30 mL) in pre-degassed flask and cooled to
À78 °C. Samarium iodide (0.1 M in pentane, 3 equiv) was added
via syringe and, after stirring for 15 min, solution was allowed
to warm up to room temperature. Solvent was removed and res-
idue was taken into EtOH/brine, and washed with brine, dried
over Na2SO4 and concentrated. Further purification was done on
column (silica gel, ꢀ100 g) using 10% ethyl acetate in hexane as
the eluent.
5.2.6. (R,S) 3
carboxylic acid methyl ester (16l)
a-Benzofuran-2-yl-8-oxa-bicyclo[3.2.1]octane-2a-
Semi solid 60% yield. 1H NMR (CDCl3). d 7.51–7.48 (m, 1H),
7.42–7.39 (m, 1H), 7.26–7.17 (m, 2H), 6.53–6.52 (m, 1H), 4.80–
4.48 (d, 1H), 4.50–4.46 (t, 1H), 3.86–3.81 (m, 1H), 3.80 (s, 3H),
3.21 (s, 1H), 2.54–2.46 (m, 1H), 2.07–2.02 (m, 1H), 1.98–1.81
(m, 2H), 1.78–1.71 (m, 1H), 1.65–1.57 (m, 1H). 13C NMR (CDCl3).
d 173.4, 160.4, 154.2, 128.6, 123.5, 122.7, 120.3, 110.8, 101.3,
75.00, 74.0, 52.2, 48.0, 30.5, 29.2, 28.4, 28.1. Mass
(M+H)+ = 287 (100%), (MÀOCH3)+ = 255 (65%), (MÀCO2CH3)+ =
227 (35%). Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found:
C, 71.39; H, 6.50.
5.2.1. (R,S) 3a-(3-(2-Furyl)phenyl)-8-oxa-bicyclo[3.2.1]octane-2
b-carboxylic acid methyl ester (16g)
White solid 65% yield, mp 94–96 °C. 1H NMR (CDCl3) d 7.54–
7.46 (m, 3H), 7.32–7.27 (t, 1H), 7.14–7.11 (d, 1H), 6.65–6.64 (dd,
1H), 6.48–6.46 (m, 1H), 4.55–4.50 (m, 2H), 3.58 (s, 3H), 3.35–
3.26 (m, 1H), 2.61–2.57 (dd, 1H), 2.49–2.40 (m, 1H), 2.20–1.95
(m, 2H), 1.85–1.76 (m, 1H), 1.73–1.64 (m, 1H), 1.50–1.42 (dt,
1H). 13C NMR (CDCl3) d 174.5, 153.9, 143.4, 142.0, 130.9, 128.7,
126.7, 122.9, 122.1, 111.6, 105.0, 74.6, 72.3, 54.9, 51.8, 36.8, 36.1,
31.6, 31.5. Mass (M+H)+ = 313 (100%), (MÀOCH3)+ = 285 (85%),
(MÀCOOCH3)+ = 253 (7%). Anal. (C19H20O4) C, H.
5.2.7. (R,S) 3a-Benzo[b]thiophen-2-yl-8-oxa-bicyclo[3.2.1]-
octane-2b-carboxylic acid methyl ester (16m)
White solid 48% yield, mp 117–119 °C. 1H NMR (CDCl3) d
7.77–7.74 (m, 1H), 7.67–7.64 (m, 1H), 7.34–7.24 (m, 2H), 7.11–
7.10 (d, 1H), 4.71–4.69 (d, 1H), 4.50–4.47 (m, 1H), 3.87–3.84
(m, 1H), 3.74 (s, 3H), 2.91–2.89 (d, 1H), 2.64–2.55 (m, 1H),
2.01–1.92 (m, 1H), 1.90–1.71 (m, 4H). 13C NMR (CDCl3)
d
173.6, 149.5, 139.8, 138.6, 124.2, 123.7, 122.9, 122.0, 119.7,
74.9, 73.4, 52.8, 52.2, 34.8, 31.6, 29.3. Mass (M+H)+ = 303
(100%), (MÀOCH3)+ = 271 (60%), (M+CO2CH3)+ = 243 (10%). Anal.
(C17H18O3S) C, H, S.
5.2.2. (R,S) 3a-(3-(2-N-Methylpyrrol)phenyl)-8-oxa-
bicyclo[3.2.1]octane-2 b-carboxylic acid methyl ester (16h)
Colorless oil 57% yield. 1H NMR (CDCl3) d 7.34–7.27 (m, 2H),
7.24–7.21 (m, 1H), 7.19–7.16 (m, 1H), 6.71–6.70 (t, 1H), 6.21–
6.19 (m, 2H), 4.70–4.66 (m, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.27–
3.21 (m, 1H), 2.89–2.77 (m, 2H), 2.1902.01 (m, 2H), 1.98–1.89
(m, 1H), 1.85–1.78 (m, 1H), 1.69–1.63 (m, 1H). 13C NMR (CDCl3) d
171.6, 142.3, 134.7, 133.0, 128.1, 127.6, 126.6, 125.6, 123.5,
108.4, 107.7, 75.4, 51.6, 51.3, 35.0, 33.4, 32.3, 29.1, 28.1. Mass
(M+H)+ = 326. Anal. (C20H23 NO3) C, H, N.
5.2.8. (R,S) 3b-Benzo[b]thiophen-2-yl-8-oxa-bicyclo[3.2.1]-
octane-2a-carboxylic acid methyl ester (16n)
Yellow oil 6% yield. 1H NMR (CDCl3) d. 7.75–7.72 (m, 1H), 7.68–
7.65 (m, 1H), 7.32–7.21 (m, 2H), 7.06 (s, 1H), 4.70–4.64 (m, 2H),
3.65 (s, 3H), 3.54–3.45 (m, 1H), 2.93–2.91 (d, 1H), 2.86–2.77 (m,
1H), 2.22–2.03 (m, 2H), 1.97–1.90 (m, 1H), 1.89–1.78 (m, 2H). 13C
NMR (CDCl3) d. 171.4, 147.5, 139.9, 138.6, 124.1, 123.6, 122.1,
119.9, 76.5, 75.3, 51.7, 45.6, 33.9, 31.1, 28.8, 28.1. Mass
(M+H)+ = 303.
5.2.3. (R,S) 3b-(3-(2-Furyl)phenyl)-8-oxa-bicyclo[3.2.1]octane-2
b-carboxylic acid methyl ester (16i)
1H NMR (CDCl3) d 7.55 (s, 1H), 7.50–7.47 (dd, 1H), 7.45–7.44
(dd, 1H), 7.32–7.27 (t, 1H), 7.17–7.14 (m, 1H), 6.63–6.62 (dd,
1H), 6.46–6.44 (m, 1H), 4.71–4.66 (m, 2H), 3.48 (s, 3H), 3.28–
3.20 (m, 1H), 2.89–2.76 (m, 2H), 2.22–1.90 (m, 3H), 1.85–1.77
(m, 1H), 1.68–1.62 (m, 1H). 13C NMR (CDCl3) d 171.6, 154.0,
142.7, 141.8, 130.6, 128.4, 126.1, 122.6, 121.8, 111.5, 104.8, 76.6,
75.3, 51.6, 51.2, 33.4, 32.2, 29.0, 28.0. Mass (M+H)+ = 313 (100%),
(MÀOCH3)+ = 285 (90%). Anal. (C19H20O4) C, H.
5.2.9. (R,S) 3
carboxylic acid methyl ester (16o)
a-(1H-Indol-2-yl)-8-oxa-bicyclo[3.2.1]-octane-2a-
Pale yellow solid 14% yield, mp 176–178 °C. 1H NMR (CDCl3) d
8.22 (s, 1H), 7.54–7.51 (d, 1H), 7.283–7.280 (d, 1H), 7.13–7.07 (m,
2H), 6.298–6.294 (d, 1H), 4.65–4.63 (d, 1H), 4.54–4.49 (m, 1H),
3.75 (s, 3H), 3.71–3.62 (m, 1H), 2.73–2.70 (dd, 1H), 2.61–2.52 (m,
1H), 2.07–1.93 (m, 1H), 1.92–1.83 (m, 1H), 1.82–1.70 (m, 3H), 13C
NMR (CDCl3) d Mass. (M+H)+ = 286. Anal. (C17H19NO3) C, H, N.
5.2.4. (R,S) 3b-(3-(2-N-Methylpyrrol)phenyl)-8-oxa-
5.2.10. (R,S) 3b-(1H-Indol-2-yl)-8-oxa-bicyclo[3.2.1]-octane-2-b-
carboxylic acid methyl ester (16p)
bicyclo[3.2.1]octane-2b-carboxylic acid methyl ester (16j)
Colorless oil 17% yield. 1H NMR (CDCl3) d 7.33–7.21 (m, 3H),
7.18–7.15 (dt, 1H), 6.72–6.71 (t, 1H), 6.22–6.19 (m, 2H), 4.54–
4.49 (m, 2H), 3.64 (s, 3H), 3.59 (s, 3H), 3.34–3.25 (m, 1H),
2.58–2.54 (dd, 1H), 2.47–2.40 (m, 1H), 2.16–2.09 (m, 1H),
2.06–1.95 (m, 1H), 1.83–1.75 (m, 1H), 1.70–1.61 (m, 1H), 1.49–
1.38 (dt, 1H). 13C NMR (CDCl3) d 174.5, 143.0, 134.6, 133.3,
128.6, 128.1, 126.8, 123.6, 108.5, 107.7, 74.6, 72.2, 55.1, 51.8,
37.1, 36.1, 35.0, 31.7, 31.6. Mass (M+H)+ = 326. Anal.
Pale yellow solid 20% yield, mp 222–224 °C. 1H NMR (CDCl3) d
8.95 (s, 1H), 7.53–7.50 (d, 1H), 7.35–7.32 (d, 1H), 7.12–7.05 (m,
2H), 6.278–6.273 (d, 1H), 4.72–4.68 (d, 1H), 4.62–4.58 (m, 1H),
3.65 (s, 3H), 3.48–3.40 (m, 1H), 2.83–2.73 (m, 2H), 2.21–2.05 (m,
2H), 2.02–1.82 (m, 2H), 1.57–1.55 (m, 1H). 13C NMR (CDCl3) d
173.4, 139.7, 136.0, 127.6, 121.2, 119.8, 119.4, 110.8, 100.5, 75.4,
51.7, 51.1, 34.2, 29.5, 29.6, 28.0. Mass. (M+H)+ = 286. Anal.
(C17H19NO3) C, H, N.
C20H23NO3) C, H, N.
5.2.11. (R,S) 3b-(1H-Indol-2-yl)-8-oxa-bicyclo[3.2.1]-octane-2-a-
carboxylic acid methyl ester (16q)
5.2.5. (R,S) 3
bicyclo[3.2.1]octane-2
a
-(3-(2-Thiazole)phenyl)-8-oxa-
Pale yellow solid 15% yield, mp decomposed > 150 °C. 1H NMR
(CDCl3) d 8.40 (s, 1H), 7.54–7.51 (d, 1H), 7.307–7.305 (d, 1H), 7.12–
7.05 (m, 2H), 6.274–6.270 (d, 1H), 4.59–4.56 (m, 2H), 3.64 (s, 3H),
3.56–3.45 (m, 1H), 3.00–2.95 (dd, 1H), 2.24–2.15 (dt, 1H), 2.09–
2.02 (m, 1H), 1.99–1.93 (m, 1H), 1.91–1.80 (m, 3H), 13C NMR
(CDCl3) d Mass. (M+H)+ = 286. Anal. (C17H19NO3) C, H, N.
a-carboxylic acid methyl ester (16k)
White solid, mp 134–135 °C. 1H NMR (CDCl3) d 7.90–7.87 (m,
2H), 7.59 (s, 1H), 7.44–7.40 (m, 3H), 7.26 (s, 1H), 4.57–4.55 (m,
2H), 3.67–3.64 (m, 1H), 3.63 (s, 3H), 3.05–3.01 (dd, 1H), 2.09–
1.97 (m, 3H), 1.96–1.87 (m, 3H). 13C NMR (CDCl3) d 171.8, 166.7,
141.8, 140.5, 133.7, 129.8, 128.9, 128.8, 128.3, 126.2, 75.9, 75.1,

2772
L. Torun et al. / Bioorg. Med. Chem. 20 (2012) 2762–2772
5.2.12. (R,S) 3a-(5-Phenyl-thiophen-2-yl)-8-oxa-
Supplementary data
bicyclo[3.2.1]octane-2a-carboxylic acid methyl ester (16r)
Colorless semi-solid. 1H NMR (CDCl3) d 7.56–7.54 (m, 2H),
7.37–7.32 (m, 2H), 7.32–7.24 (m, 1H), 7.13–7.11 (d, 1H), 6.85–
6.84 (m, 1H), 4.68–4.66 (m, 1H), 4.50–4.48 (m, 1H), 3.79–3.69
(m, 4H), with a singlet at 3.74 for 3H), 2.82–2.80 (dd, 1H),
2.62–2.52 (m, 1H), 1.99–1.75 (m, 5H). 13C NMR (CDCl3) d:
173.8, 148.2, 141.9, 134.3, 128.8, 127.2, 125.4, 124.2, 123, 74.9,
73.3, 53.3, 52.2, 35.2, 31.2, 29.5. Mass (M+H)+ = 329 (100%). Anal.
(C19H20O3S) C, H, S.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2012.01.053. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
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carboxylic Acid Methyl Ester (16t)
Pale yellow oil, 74% yield. 1H NMR (CDCl3) d 7.09–7.06 (m,
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5.2.15. (R,S) 3
carboxylic Acid Methyl Ester (16u)
a-Thiophen-2-yl-8-oxa-bicyclo[3.2.1]octane-2a-
White solid 9% yield, mp 102–103 °C. 1H NMR (CDCl3) d 7.12–
7.10 (dd, 1H), 6.93–6.90 (m, 1H), 6.84–6.83 (m, 1H), 4.67–4.60
(m, 2H), 3.57 (s, 3H), 3.48–3.41 (m, 1H), 2.86–2.84 (d, 1H), 2.78–
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5.3. Biology
The affinities of 2,3-unstaurated ‘ene’ and 2,3-saturated ‘ane’
compounds for the DAT and SERT are presented in Tables 3 and
4, respectively. The affinities (IC50) for the dopamine and serotonin
transporters were determined in competition studies using [3H]3b-
(4-fluorophenyl)tropane-2b-carboxylic acid methyl ester (WIN
35,438) or [3H]CFT) to label the DAT and [3H]citalopram to label
the serotonin transporter. Nonspecific binding was measured with
fluoxetine (10 l
M).41 Each compound was tested 2–5 times in
monkey striatum because these compounds were part of an ongo-
ing SAR study of DAT in this tissue.9,21–23,29–31 Competition studies
were conducted with a fixed concentration of radioligand and a
range of concentrations of test drug. All compounds inhibited
[3H]WIN 35,438 and [3H]citalopram in a concentration dependent
manner. All compounds tested are racemic.
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Acknowledgment
40. Meltzer, P. C.; Blundell, P.; Huang, H.; Liu, S.; Yong, Y. F.; Madras, B. K. Bioorg.
Med. Chem. 2000, 8, 581.
41. Davies, H. M. L.; Gilliatt, V.; Kuhn, L. A.; Saikali, E.; Ren, P.; Hammond, P. S.;
Sexton, T.; Childers, S. R. J. Med. Chem. 2001, 44, 1509.
We thank the National Institute on Drug Abuse for financial
support (DA 11542, DA 7-8825, DA 06303).