Synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters

Article abstract of DOI:10.1016/j.tetlet.2005.10.170

Cross coupling protocols were applied for the synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl esters. Stille conditions produced the corresponding products in reasonable yields. Samarium iodide reduction of the resulting coupling products produced the 2β-carbomethoxy-3α-aryl-8-oxabicyclo[3.2.1]octane diastereoisomers as the major, and the 2β-carbomethoxy-3β-aryl-8- oxabicyclo[3.2.1]octane diastereoisomer as the minor products. Both diastereomers manifested inhibition of the dopamine (DAT) and serotonin (SERT) transporters, with some selectivity for SERT inhibition.

Full text of DOI:10.1016/j.tetlet.2005.10.170

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 599–603
Synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]octane-
2-carboxylic acid methyl esters
Lokman Torun,a Shanghao Liu,a Bertha K. Madrasb and Peter C. Meltzera,*
aOrganix Inc., 240 Salem Street, Woburn, MA 02801, USA
bNew England Regional Primate Research Center, Southborough, MA 01772, USA
Received 28 September 2005; revised 25 October 2005; accepted 25 October 2005
Available online 1 December 2005
Abstract—Cross coupling protocols were applied for the synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]oct-2-ene-2-carbox-
ylic acid methyl esters. Stille conditions produced the corresponding products in reasonable yields. Samarium iodide reduction of the
resulting coupling products produced the 2b-carbomethoxy-3a-aryl-8-oxabicyclo[3.2.1]octane diastereoisomers as the major, and
the 2b-carbomethoxy-3b-aryl-8-oxabicyclo[3.2.1]octane diastereoisomer as the minor products. Both diastereomers manifested inhi-
bition of the dopamine (DAT) and serotonin (SERT) transporters, with some selectivity for SERT inhibition.
Ó 2005 Elsevier Ltd. All rights reserved.
The discovery and development of potential medications
for cocaine abuse has focused to a large extent on the
diverse family of bicyclo[3.2.1]octanes.1–3 These com-
pounds bind potently to monoamine uptake mecha-
nisms in the mammalian system (dopamine (DAT),
serotonin (SERT) and norepinephrine (NET) transport-
ers) and these systems have been implicated in the phar-
macology of addiction caused by cocaine, itself a
bicyclo[3.2.1]octane. In particular, the stimulatory and
addictive properties of cocaine have been thought to
be largely due to its ability to inhibit the DAT,4–9
although the SERT has also been implicated.10–13
within the 8-oxabicyclooctane series. In this regard,
Davies et al.16 and Fu et al.17 have reported the synthesis
and biological effects of 3-heterobiaryl systems in the
8-azabicyclo[3.2.1]octane series. They found that the
introduction of 4-(2-pyrrolyl)phenyl16 and 4-(2-thiophen-
yl)phenyl17 caused these molecules to increase binding
potency at SERT and decrease binding potency at
DAT, thus providing compounds in which the DAT
vs. SERT selectivity of the monoaryl compounds had
been reversed. We now present the synthesis of a series
of 3-(4-heteroarylphenyl)-8-oxa-2-carbomethoxybicyclo-
[3.2.1]octanes.
In an extensive investigation aimed at developing medi-
cations for cocaine abuse, we have shown that the DAT
and SERT inhibitory potency of the bicyclo[3.2.1]octane
system is not limited by the nature of the heteroatom at
the 8-position. While cocaine and its potent 3-aryl cong-
eners 1 (Fig. 1) are 8-azabicyclo[3.2.1]octanes, we have
demonstrated that 8-carba,14 8-oxa14 and 8-thia15 bicy-
clo[3.2.1]octanes (2–4) have significant potency in inhibi-
tion of monoamine transport and are often equipotent
to their 8-aza counterparts.1 In our search for SERT
selective uptake inhibitors we have now explored the
introduction of heteroaryl moieties on the 3-aryl ring
The synthesis of 8-oxabicyclooctanes such as 3 has been
described in detail previously.18 The route that we had
developed utilized a Suzuki coupling of the vinyltriflate
24 (Scheme 2) with appropriate arylboronic acids. The
4-bromophenyl compound (Scheme 1) 5 was available
via this route, so we initially planned to utilize 5 in a sec-
ond Suzuki coupling to obtain 10–12. To our surprise,
Suzuki conditions (Pd(PPh3)4, LiCl, Na2CO3, CH2Cl2)
did not produce any product with 2-furanboronic acid,
6. Furthermore, only a low yield (36%) of 11 was ob-
tained with 7 under these conditions. However, Stille
coupling of 5 with both 8 and 9 proved successful (56–
61%).
Keywords: Oxatropanes; Cocaine antagonist; Suzuki coupling; Stille
coupling; SmI2.
A more general synthesis of the bicyclooctanes 10–13
was developed and is shown in Scheme 2. Since 2418 is
readily available in our laboratories, we elected to use
*
Corresponding author. Tel.: +1 781 932 4142; fax: +1 781 933
6695; e-mail: Meltzer@organixinc.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.170

600
L. Torun et al. / Tetrahedron Letters 47 (2006) 599–603
CH2
CH3N
CH3N
O
S
CO2CH3
O
CO2CH3
CO2CH3
CO2CH3
CO2CH3
Cl
Cl
Cl
R
Cl
Cl
Cl
1
3
4
Cocaine
2
O
Figure 1.
Pd(PPh3)4, LiCl, Na2CO3
DEM, reflux
X
B(OH)2
O
6
7
X = O, 34h, 0%
X = S, 32h, 36%
or
O
CO2CH3
CO2CH3
X
Br
X
5
SnBu3
10 X = O
11 X = S
8
9
X = O, 1h, 56%
12 X = NCH3
X = NCH3, 4h, 61%
Pd(PPh3)4, Dioxane, reflux
Scheme 1. Application of Suzuki and Stille protocols to the synthesis of 10–12.
1) n-BuLi, THF,
-78˚C to -20˚C
2) Bu3SnCl
Br
X
Y
X
X
Bu3Sn
I
Br
Bu3Sn
Y
Y
or Pd(PPh3)4, (Bu3Sn)2,
dioxane
Y = C
Pd(PPh3)4, dioxane
20 X = O
21 X = S
Y = C
Y = C
16
17
18
X = O
8
X = O
Y = C
Y = C
X = S
Y = C
14 X = S
X = NCH
22 X = NCH
23 X = S
3 Y = C
Y = N
X = NCH
9
3 Y = C
Y = N
3 Y = C
Y = N
19 X = S
15 X = S
O
CO2CH3
OSO2CF3
O
CO2CH3
X
Y
24
Pd2dba3, ZnCl2,
tris(2-furyl)phosphine,
NMP, rt, 18h
10 X = O, Y = C : 82%
11 X = S, Y = C : 75%
12 X = NCH3, Y = C : 79%
13 X = S, Y = N, 79%
Scheme 2. Synthesis of biaryl-8-oxatropenes 10–13.
Stille coupling with appropriate stannanes to obtain the
target compounds. Thus coupling of the arylstannanes
8, 9, 14, 15 with 1-bromo-4-iodobenzene, with
Pd(PPh3)4 as catalyst, provided the biaryl compounds
16–19, which were purified by column chromatography
(40–87%). Treatment with n-BuLi at À70 °C in THF
for 1 h, followed by addition of tributyltin chloride
then provided the tributylstannyl compounds 20–23.
Attempts to purify these stannyl compounds resulted
in substantial decomposition. Consequently they were
used in the following reactions without purification.
The bicyclooxatropenes 10–13 were then obtained by a
second Stille coupling. Thus cross coupling of the triflate
2418 with the arylstannane building blocks 20–23 was
carried out at room temperature in 1-methyl-2-pyrrolid-
inone (NMP) in the presence of Pd2dba3, tris-(2-
furyl)phosphine and ZnCl2. Treatment of the crude

L. Torun et al. / Tetrahedron Letters 47 (2006) 599–603
601
reaction mixture with 10% aq KF greatly simplified the
removal of tin byproduct by transforming it into insolu-
ble tributyltin fluoride, which can be removed by filtra-
tion. The products were obtained in high yields (75–
82%) after flash column chromatography on silica gel
with ethyl acetate/hexane (1:9) as the eluent. When nec-
essary, products were further purified by recrystalliza-
tion. Characterization was performed by 1H NMR
spectroscopy, mass spectrometry and elemental analysis.
in many ways. However, methods such as catalytic
hydrogenation result in reduction occurring from the
b-face, thus resulting in 2a,3a-configured compounds.
The most effective manner in which to obtain both the
boat and chair 2b-carbomethoxy configured compounds
has proved to be by the use of the single electron transfer
21–23
reducing agent SmI2
in a solvent such as metha-
nol.18,24 Thus, samarium iodide reduction of 10–13 in
10% methanol in tetrahydrofuran at À78 °C provided
the 2b-carbomethoxy-3a-aryl (boat) compounds in rea-
sonable yield with the exception of 25d for which only
a 9% yield was achieved (Scheme 3). The 2b-carbome-
thoxy-3b-aryl (chair) diastereomers were obtained in
substantially lower yields for 26a and 26c while 26b
and 26d were not obtained. In the latter case, the major
product proved to be the 2a-COOCH3, 3a-aryl boat
configured compound. Unfortunately the 2a-COOCH3
diastereomers are often biologically uninteresting since
they generally bind poorly at monoamine uptake sys-
tems.1,19 Separation was achieved by column chromato-
graphy on silica gel using 10% ethyl acetate in hexane.
1
The H NMR spectra of these compounds are diagnos-
tic (Table 1). In particular the H1 proton appears as a
doublet between d 4.96–5.02 while H5 is a multiplet at
d 4.64–4.68. Furthermore, H4b appears as a double
doublet at d 2.95–3.08 with the H4a proton as a doublet
at d 2.14–2.28.
Earlier structure–activity relationship studies have
pointed conclusively to the fact that the biologically
interesting isomers within the broad class of bicyclo-
[3.2.1]octanes have certain stereospecific require-
ments.1,18,19 In particular, the 2b-carbomethoxy-3b-aryl
(chair) configured compounds generally manifested po-
tency at both DAT and SERT. In contrast, the 2b-carbo-
methoxy-3a-aryl (boat) compounds were generally far
less potent at SERT. This lesser potency at SERT was
also the case in the 2,3-unsaturated class of compounds
to which 10–13 belong.20 For these reasons we were par-
ticularly interested in obtaining the 2b-carbomethoxy-
3b-aryl (chair) configured compounds. We anticipated
that these would be inherently more potent at inhibition
of the SERT, and in this new class of compounds that
potency at SERT may be further enhanced by the pres-
ence of the new heteroaryl substituent. Reduction of
the 2,3-unsaturated compounds 10–13 can be affected
1
Yields are given in Table 2. Again, H NMR spectro-
scopy was diagnostic for these compounds. The stereo-
chemistry at the 2- and the 3-positions was established
by the characteristic coupling constants and chemical
shifts of the corresponding protons (Table 1). These
are in good agreement with published work from our
group.18 Specifically, 3a-aryl compounds manifest a
double double doublet for H4a at about d 1.4 whereas
3b-aryl compounds present a multiplet at d 1.9 for this
proton. The proton at H2 is also diagnostic in that 3a-
aryl compounds manifest a double doublet at about d
2.6 whereas 3b-aryl compounds have doublet at about
d 2.8.
Table 1. Physical and spectral dataa
Compd
Melting point (°C)
Yield (%)
1H NMR (d ppm) diagnostic peaks (J Hz)
2,3-Enes
H1 (d)
5.01
5.02
5.01
4.96
H5 (m)
4.64
4.65
4.67
4.68
H4a (dd)
2.15
2.14
2.17
2.28
H4b (d)
2.95
2.96
2.96
3.08
10
11
12
13
107–108
111–112
Oil
82
75
79
79
Oil
3-a-Aryl
25a
25b
H1,5 (m)
4.4–4.5
4.4–4.5
4.5–4.6
4.5–4.6
H2 (dd)
2.55
2.56 (10.1, 2.2)
2.58 (10.2, 2.2)
2.57 (10.1, 2.4)
H3 (dt)
3.27
3.28
3.29
3.32
H4a (ddd)
1.41
1.41
1.44
1.44
H4b
2.40
2.40
2.45
2.45
130–131
136–138
Oil
53
79
54
9
25c
25d
112–114
3-b-Aryl
26a
26c
H1,5 (m)
4.6–4.7
4.6–4.7
H2 (d)
2.85 (5.2)
2.87 (5.2)
H3 (dt)
3.23
3.24
H4a (m)
1.9
1.9
H4b (dt)
2.79
2.80
140–142
Oil
21
22
Doublet (d), multiplet (m), double doublet (dd), double double doublet (ddd).
a Spectra measured in CDCl3.
O
CO2CH3
O
O
CO2CH3
CO2CH3
SmI2
R
R
+
THF:MeOH (9:1);
-78˚C
R
10-13
25
26
Scheme 3. SmI2 reduction of 3-biaryl-2-carbomethoxybicyclo[3.2.1]oct-2-enes.

602
L. Torun et al. / Tetrahedron Letters 47 (2006) 599–603
Table 2. Distribution of diastereomers obtained from samarium iodide reduction
O
CO2CH3
O
CO2CH3
R
R
25
26
Compound
R
Yield (%)
53
Compound
R
Yield (%)
21
O
S
O
S
25a
26a
25b
25c
79
54
26b
26c
Not obtained
22
CH3
N
CH3
N
S
N
S
N
25d
9
26d
Not obtaineda
a The 2a-COOCH3-3a-aryl boat configured compound was the major product (25%).
It is noteworthy that within the series of 8-oxabicy-
clo[3.2.1]octanes, the 3a-aryl compounds are generally
formed in higher yields than the 3b-aryl compounds.18
Indeed, in the case of the reduction of 11 and 13, the
3b-aryl compound 26b and 26d were not isolated at
all. Only the 3a-aryl 25b was obtained (79%), while 13
yielded a major product in which the 2-COOCH3 was
isomerized to the 2a-configuration. The reasons for the
general dominance of the 3a-aryl over the 3b-aryl are
unclear. Possibly, a preference for 3a-aryl reduced prod-
ucts might be dominated by an intermediate species in
which the samarium is coordinated to the bridge oxy-
gen, and probably to the C2-carbomethoxy group. It
may then be surmised that proton transfer occurs pref-
erentially from the b-face of the molecule to provide,
predominantly, the 3a-aryl substituent.
itors of the SERT. However, in contrast to the parent 8-
oxatropanes,18 both the boat and chair compounds
manifested some selectivity versus inhibition of the
DAT.
A series of (R,S) 3-(4-heteroarylphenyl)-8-oxabicyclo-
[3.2.1]carboxylic acid methyl esters were synthesized
via Stille coupling. Samarium iodide reduction of the
bicyclooctenes produced the 3a-aryl diastereomer pre-
dominantly over the 3b-aryl diastereomer. Both 3a-aryl
and the 3b-aryl diastereomers manifest a preferential
inhibition of the serotonin transporter compared with
their inhibition of the dopamine transporter.
Acknowledgement
The IC50 values for inhibition of the dopamine trans-
porter (DAT) and the serotonin transporter (SERT
are shown in Table 3). It is noteworthy that the reduced
compounds 25 and 26 were generally more potent inhib-
We thank the National Institute on Drug Abuse for
financial support (DA 11542, DA 7-8825, DA 06303).
Supplementary data
Table 3. Inhibition of [3H]WIN 35,428 binding to the human
dopamine transporter (hDAT) and [3H]citalopram binding to the
human serotonin transporter (hSERT)a
The supplementary data, including full experimental
details, are available. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.10.170.
Compound DAT IC50 (nM) SERT IC50 (nM) DAT/SERTb
10
11
102
272
>10,000
>5,000
139
248
242
>10,000
>14,000
32
0.4
1.1
1
12
13
References and notes
1
25a
25b
25c
25d
26a
26c
4.3
10.2
2.5
13.8
2.1
21.9
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