Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives

Article abstract of DOI:10.1016/j.bmc.2006.07.051

A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3α derivatives were found to be the most potent compounds with

Full text of DOI:10.1016/j.bmc.2006.07.051

Bioorganic & Medicinal Chemistry 14 (2006) 7943–7952
Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-
8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives
Suhong Zhang,a Sari Izenwasser,b Dean Wade,b Liang Xua and Mark L. Trudella,*
aDepartment of Chemistry, University of New Orleans, USA
bDepartment of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, USA
Received 26 May 2006; revised 19 July 2006; accepted 26 July 2006
Available online 14 August 2006
Abstract—A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3
were synthesized and evaluated at dopamine and serotonin transporters. The 3a derivatives were found to be the most potent com-
pounds with the 3a-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most
potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-
2-ene 12b (Ki = 12 nM) was slightly less potent than the 3a-analogue, while the 3b-di(4-fluorophenyl)methoxymethyl-8-(3-phenyl-
propyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3a-ana-
logue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine
transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss
in potency. In addition, the structure–activity data for these tropane-GBR 12909 hybrid analogues support previous findings that
the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity
over the serotonin transporter.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
template to investigate the structural requirements for
high-affinity and selective binding to the dopamine
transporter (DAT) as well as to identify new lead com-
pounds for medications development.11–22
The abuse of cocaine still remains a serious social and
economic problem in the United States. However, de-
spite an increasing population of users and abusers there
is no effective medication available for the treatment of
cocaine addiction.1 Efforts to develop a cocaine thera-
peutic have been primarily focused upon the identifica-
Recent studies in our laboratories have identified
3-diarylmethoxyethylidenyl-8-(3-phenylpropyl)-8-azabi-
cyclo[3.2.1]octanes (2) as potent and selective ligands for
the DAT.23 The 3-ethylidenyltropanes 2 were slightly
more potent than GBR 12909 but were more selective
for the DAT over the serotonin transporter (SERT).
The unsaturated analogues 2 exhibited similar potency
to that of the corresponding 3a-tropane congeners 3
but were significantly more selective for the DAT than
3.23 Based upon the structure–activity relationships of
2 and related tropane analogues 3, the high DAT selec-
tivity of 2 appeared to be derived from either the con-
formationally rigid 3-ethylidenyltropane ring system or
the stereochemical effects imparted by unsaturation at
C3. To investigate further the effects of unsaturation
and stereochemistry at C3 of these tropane-GBR 12909
hybrid analogues on DAT and SERT binding affinities,
a series of 3-diarylmethoxymethyl-8-arylalkyl-8-azabicy-
clo[3.2.1]oct-2-enes (4) have been designed and synthe-
sized. It is envisaged that if unsaturation at C3 is
tion of
a selective dopamine transporter uptake
inhibitor to be used in a cocaine substitution therapy.2,3
Although a wide variety of structurally diverse com-
pounds have been prepared and studied,2–4 the disubsti-
tuted piperazine GBR 12909 (1)5–7 and related
derivatives have shown some of the greatest potential
for development of a dopamine uptake inhibitor thera-
peutic agent for cocaine addiction.8–10 While GBR
12909 has yet to be established as a clinically useful ther-
apeutic for the treatment of cocaine addiction, numer-
ous laboratories have employed GBR 12909 as a
Keywords: Cocaine; Tropane; Dopamine transporter; Serotonin
transporter.
*
Corresponding author. Tel.: +1 504 280 7337; fax: +1 504 280
6860; e-mail: mtrudell@uno.edu
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.07.051

7944
S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
X
F
N
N
O
N
O
GBR12909 (1)
2a X = H
2b X = F
X
F
X
X
R
N
R
N
N
O
O
X
X
3a
3b
5 (α and β)
X = H
X = F
X
4
O
X
Figure 1.
important in these tropane systems for high DAT selec-
tivity, then the tropene congeners 4 would be expected
to exhibit similar DAT selectivity to that observed for
the 3-ethylidinyltropanes 2. However, if unsaturation
and conformational rigidity at C3 is not as important
as the relative proximity and conformation of the ethy-
lidenyl benzhydryl ether moiety to the tropane ring sys-
tem, then tropene analogues 4 may exhibit DAT
selectivity more similar to GBR 12909 and the 3a-tro-
pane derivatives 3. In addition, to address further the
question of stereochemical proximity of the benzhydryl
ether moiety relative to DAT affinity, the 3a- and 3b-
diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]oc-
tane derivatives 5 have been designed and synthesized to
evaluate the stereochemical/proximity effects of the benz-
hydryl ether moiety relative to the tropane ring system.
Herein, we describe the synthetic details and in vitro
pharmacological profile at the DAT and SERT of a
series of 3-diarylmethoxymethyl-8-arylalkyl-8-azabicy-
clo[3.2.1]oct-2-ene and 3-diarylmethoxymethyl-8-aryl-
alkyl-8-azabicyclo[3.2.1]octane derivatives (Fig. 1).
Selective reduction of the ester moiety of 7 with lithium
aluminum hydride was achieved in THF at 0 ꢁC to fur-
nish the alcohol 8 in 60% yield. The diaryl ethers 9a and
9b were obtained in 80% and 87% yields, respectively, by
simply heating the alcohol 8 neat at 160 ꢁC with the cor-
responding diaryl methylchloride. This procedure origi-
nally developed for the synthesis of benztropine
analogues was found to work exceptionally well in these
homologous tropane systems.25 Removal of the carba-
mate moiety with hydrazine hydrate in ethylene glycol
then furnished the secondary amines 10a (71%) and
10b (77%) in good yield. Treatment of 10a and 10b with
either benzyl bromide or 1-bromo-3-phenylpropane in
DMF afforded the corresponding derivatives 11a, 11b
and 12a, 12b in 81–88% yield. Alternatively, N-methyla-
tion of 10a and 10b was achieved by reductive amination
with aqueous formaldehyde and sodium cyanoborohy-
dride in acetonitrile at room temperature to furnish
13a and 13b, both in 81% yield.
The synthesis of the 3a-diarylmethoxymethyl-8-aryl-
alkyl-8-azabicyclo[3.2.1]octane derivatives was achieved
by hydrogenation of the C2–C3 double bond of the cor-
responding 3-diarylmethoxymethyl-8-arylalkyl-8-azabi-
cyclo[3.2.1]oct-2-ene under ambient conditions over
10% palladium on carbon in methanol (Scheme 1). The
3a-tropane derivatives 14a, and 15a, 15b, 16a, 16b were
obtained stereoselectively as single diastereoisomers in
greater than 90% yield. It was interesting that attempts
to convert 11b into 14b under similar conditions gave
only saturated and debenzylated material. Therefore, to
overcome this anomalous reactivity the 3a-tropane deriv-
ative 14b was prepared by an alternative route illustrated
at the bottom of Scheme 1. Hydrogenation of the second-
ary amine 10b gave the 3a-nortropane 17 as single dia-
stereoisomer and N-alkylation with benzyl bromide
furnished 14b in 78% overall yield.
2. Chemistry
The syntheses of the 3-diarylmethoxymethyl-8-arylalkyl-
8-azabicyclo[3.2.1]oct-2-ene and 3a-diarylmethoxymeth-
yl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives were
envisaged to proceed from 3-carbomethoxy-8-methyl-
8-azabicyclo[3.2.1]oct-2-ene (6), which is readily avail-
able from tropinone.24 As illustrated in Scheme 1,
demethylation of 6 with ethyl chloroformate in toluene
at reflux afforded the carbamate 7 in 95% yield. The
removal of the methyl group and introduction of the
carbamate served to reduce the basicity of the bridging
nitrogen atom of 7, which greatly facilitated the isola-
tion and purification of subsequent intermediates.

S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
7945
CO2Et
N
CO2Et
N
H3C
N
i
ii
iii
CO2CH3
CO2CH3
OH
8
6
7
CO2Et
N
H
N
R
N
X
X
iv
X
v or vi
O
O
O
9a X = H
9b X = F
10a X = H
10b X = F
X
X
X
X = H, R = CH2Ph
X = F, R = CH2Ph
X = H, R = (CH2)3Ph
11a
11b
12a
12b X = F, R = (CH2)3Ph
13a X = H, R = CH3
13b X = F, R = CH3
H
R
N
N
v
vii
vii
11a
12a
12b
13a
13b
10b
H
H
O
(to 14b)
(to 14b)
O
X
F
F
X
14a X = H, R = CH2Ph
14b X = F, R = CH2Ph
15a X = H, R = (CH2)3Ph
17 R = H
15b
16a
16b
X = F, R = (CH2)3Ph
X = H, R = CH3
X = F, R = CH3
Scheme 1. Reagents and conditions: (i) ClCO2Et, K2CO3, toluene, reflux; (ii) LiAlH4, THF, 0 ꢁC; (iii) ClCH(4-X–C6H5)2, 160 ꢁC; (iv) KOH,
NH2NH2H2O, HOCH2CH2OH, reflux; (v) RBr, K2CO3, DMF, 80–85 ꢁC; (vi) 37% HCHO, CH3CN, NaCNBH3; (vii) H2, 10% Pd/C, CH3OH.
The 3b-diarylmethoxymethyl-8-arylalkyl-8-azabicy-
clo[3.2.1]octane derivatives were synthesized from the
readily available 3b-tropane carboxylic acid (18)
(Scheme 2). Reduction of the carboxyl group of 18 with
lithium aluminum hydride in THF at À78 ꢁC to room
temperature gave alcohol 19 as a mixture of C3-isomers
(a:b, 1:8). Without separation of the isomers, the alcohol
19 was heated at 150 ꢁC neat with the corresponding
diaryl methylchloride. This afforded a mixture of
3a- and 3b-tropane ethers that were easily separated
by column chromatography to furnish the 3b-diaryl-
methoxymethyl-8-methyl-8-azabicyclo[3.2.1]octane
derivatives 20a and 20b in 60% and 67% overall yield,
respectively. The 3a-isomers 16a and 16b were each also
obtained in 8% yield.
21 from 20 by using a-chloroethyl chloroformate
(ACE-Cl), even under vigorous conditions, were unsuc-
cessful. Treatment of 21a and 21b with either benzyl
bromide or 1-bromo-3-phenylpropane afforded the cor-
responding derivatives 22a, 22b, and 23a, 23b in 76–
78% yield.
3. Results and discussion
The DAT and SERT binding affinities were determined
for the tropene and tropane analogues by their ability to
displace bound radiolabeled ligands from rat caudate-
putamen tissue.26 The Ki values that are reported in
Table 1 are inhibition constants derived for the unla-
beled ligands. The binding affinities of the tropene and
tropane analogues were determined at DAT by inhibi-
tion of [3H]WIN 35,428 binding.26 For compounds that
exhibited potent DAT affinity with Ki values less than
100 nM, the inhibition of [3H]dopamine uptake
(DUI)26 and the SERT affinity (inhibition of [3H]citalo-
pram binding) were determined.
The N-phenylpropyl and N-benzyl substituted 3b-iso-
mers were prepared by treatment of methyl congeners
20a and 20b with ethyl chloroformate with concomitant
decarbonylation using hydrazine hydrate to give the
secondary amines 21a (67%) and 21b (74%) in good
overall yields (Scheme 2). Attempts to directly prepare

7946
S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
X
H3C
H3C
H3C
N
N
N
ii
i
CO2H
OH
O
H
X
18
19 (α : β, 1:8)
20a X = H
20b X= F
X
X
H
R
N
N
iii, iv
v
O
O
X
X
21a X = H
21b X= F
22a X = H, R = CH2Ph
22b X = F, R = CH2Ph
23a X = H, R = (CH2)3Ph
23b
X = F, R = (CH2)3Ph
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, 0 ꢁC; (ii) ClCH(4-X–C6H5)2, 150 ꢁC; (iii) ClCO2Et, K2CO3, toluene, reflux; (iv) KOH,
NH2NH2ÆH2O, HOCH2CH2OH, reflux; (v) RBr, K2CO3, DMF, 80–85 ꢁC.
Table 1. In vitro binding data at the DAT, the SERT and dopamine uptake inhibition
Compounda
[3H]WIN 35,428
(DAT) Kib (nM)
[3H]DA (DUI)
[3H]Citalopram
(SERT) Kib (nM)
DAT/SERT
b
IC50 (nM)
1
2a
12
2
34c
327
152
42
4.1 0.6
3.7 0.4
3.3 0.6
2.1 0.2
1340 240
563 200
750 41
2b
3a
18
2
15 4
5.4 1.1
3b
7.4 3.0
732 22
441 73
219 56
175 23
24
11a
11b
12a
12b
13a
13b
14a
14b
15a
15b
16a
16b
20a
20b
22a
22b
23a
23b
12
3
9.1 2.0
553 89
48
1678 25
208 18
167 35
151
67
8
9
21
5.2 1.7
6
595
101 10
9
9
20
5.1 1.3
280 23
46
5
37
39
6
998 137
22
1612 65
327 65
2255 192
684 37
359 37
78
5
8
310 68
5
a All compounds were tested as the oxalate salt.
b All values are means SEM of three experiments each performed in triplicate.
c Value reproduced from Ref. 22.
As summarized in Table 1, the 3a-diarylmethoxymethyl-
8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives 14, 15,
and 16 were found to be the most potent compounds
of the class at dopamine transporters. The 3a-di(4-fluor-
ophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicy-
clo[3.2.1]octane 15b (Ki = 5 nM) was the most potent
compound of the series and was equipotent with the tro-
pane-GBR hybrid analogues 2b and 3b that have been
reported previously.16,23 The corresponding 3-diaryl-
methoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]oct-2-ene
analogues 11, 12, and 13 were generally less potent than
the 3a-analogues; however, 3-di(4-fluorophenyl)meth-
oxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-
ene 12b (Ki = 12 nM) exhibited only slightly diminished
DAT affinity relative to 15b and was equipotent with
GBR 12909 (1). The 3b-diarylmethoxymethyl-8-aryl-
alkyl-8-azabicyclo[3.2.1]octane derivatives 22 and 23
were significantly less potent at DAT than the

S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
7947
unsaturated and 3a-isomers. Only the 3b-di(4-fluor-
ophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabi-
cyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited modest
affinity for the dopamine transporter (e.g., DAT binding
affinity 15b > 12b > 23b). The trend in DAT affinity for
the unsaturated and 3a isomers was expected, given that
2b was slightly more potent than the 3a analogue 3b.
However, the 3b-isomers 22 and 23 are the first reported
ligands within the tropane-GBR 12909 hybrid series that
possess b-stereochemistry at the 3-position. As such, the
16-fold reduction in potency of the 3b-isomer 23b was
not anticipated based on the stereochemical SAR of co-
caine and the 3b-aryltropanes at the DAT. Within these
two ligand classes, the 3b-isomers generally exhibited
significantly higher affinities than the 3a-congeners.2–4,27,28
Based upon these results, the tropane-GBR12909 hybrid
stereoselectivity at dopamine transporters appears to be
more similar to that observed for derivatives of
benztropine than that observed for derivatives of
cocaine.29
that generally exhibit modest to high selectivity for
DAT over SERT or norepinephrine transporters.16–23
However, it has been reported recently that DAT selec-
tivity among piperidine-based GBR hybrids can be
attenuated by substitution of the N-phenylpropyl side
chain.22 The unsaturated analogue 12b (SERT/
DAT = 48) exhibited the greatest selectivity for the
DAT of this series, while the 3b-isomer 23b (SERT/
DAT = 5) had the lowest selectivity. Although the
potency of 23b was low, the transporter selectivity of
the 3b-isomer 23b is noteworthy and suggests that the
3b-tropane-GBR 12909 hybrids may be viable targets
for the development of dual or multi-site monoamine
transporter inhibitors that could have therapeutic appli-
cations not only for drug abuse but also for the treat-
ment of depression and anxiety.31 The SERT/DAT
selectivity observed for the analogue 12b is in agreement
with previous findings in the diarylmethoxyethylidenyl-
tropane series (2) that indicated unsaturation at C3 re-
duced SERT affinity thus increasing DAT selectivity,
albeit 12b was significantly less selective than 2b
(SERT/DAT = 152). Based upon the SERT/DAT selec-
tivities, it appears that for these tropane-GBR hybrids
the exo-cyclic carbon–carbon double bond of 2b is less
well tolerated by the SERT than the endo-cyclic double
bond of 12b. This may be in part due to greater confor-
mational freedom of the diaryl ether moiety imparted by
the endo-cyclic double bond. As such the more flexible
benzhydryl ether moiety can readily adopt a favorable
conformation for binding at the SERT. For this reason,
the 3a-congeners 3b and 15b exhibit greater affinity for
the SERT than 12b and are less selective for the DAT
than 12b.
In general, N-(3-phenylpropyl) derivatives 12, 15, and 23
were more potent than N-methyl derivatives 13, 16, and
20, which in turn were more potent than the N-benzyl
derivatives 11, 14, and 22. This trend is consistent with
GBR analogues but differs for benztropines, which fa-
vor N-methyl substitution,29 and piperidine-based
GBR hybrids, which favor N-benzyl substitution.3 Like-
wise ligands 12b, 15b, and 23b with fluorine substitution
on the benzhydryl ether moiety exhibited greater DAT
affinity than the desfluoro-congeners 12a, 15a, and
23a. This trend was consistent with the established
SAR for the tropane-GBR 12909 hybrids. However,
there was greater difference in DAT affinity between
the diarylmethoxymethyl analogues (12a:12b, 15a:15b,
16a:16b, and 23a:23b) than previously observed for the
diarylmethoxyethylidinyl-tropanes (2a:2b) and 3a-
diarylmethoxyethyltropane analogues (3a:3b). These
results are also similar to those reported for the benztro-
pines,29 while a similar effect of fluorine substitution is
not observed for the SAR of piperidine-based GBR
analogues.3,30
In summary, we have prepared a series of diarylmeth-
oxymethyltropane-GBR hybrid analogues with all
three possible stereochemical orientations at C3. In
general, the diarylmethoxymethyltropane-GBR hybrid
analogues exhibited similar DAT structure–activity
to that previously reported 3a-diarylmethoxyethyl-
and 3-diarylmethoxyethylidinyltropane analogues.16,23
These results support our hypothesis that the stereo-
chemical and conformational effects imparted by
unsaturation at C3 are important for selectivity at
the dopamine transporter over the serotonin trans-
porter. This is supported further by the SAR of
3a-isomers in this series, which despite the reduced
tether length between the benzhydryl ether moiety
and the tropane ring system exhibited similar DAT
binding affinity to the 3-diarylmethoxyethylidinyltro-
panes but were less selective for DAT over SERT.
This suggests that the dopamine transporter can toler-
ate some variability in proximity of the benzhydryl
ether to the basic nitrogen atom of the tropane with-
out loss in potency. Only compounds that possessed
3b-stereochemistry were less well accommodated by
transporter constraints for potent molecular recogni-
tion. Overall this investigation suggests subtle changes
in molecular topology can lead to dramatic changes in
monoamine transporter selectivity. The degree to
which these changes are manifested in cocaine behav-
ioral paradigms is currently under investigation and
will be reported in due course.
Those compounds (12b, 15a, 15b, 16b, and 23b) that
exhibited potent DAT affinities were evaluated for inhi-
bition of dopamine uptake. The IC50 values determined
for [3H]dopamine uptake inhibition were generally of
similar potency to the Ki values for inhibition of DAT
binding of [3H]WIN 35,428. This select group of com-
pounds was also evaluated at serotonin transporters
for inhibition of [3H]citalopram binding. All of the com-
pounds exhibited poor SERT binding affinity
(Ki > 100 nM). The proximity of the benzhydryl ether
to the tropane ring due to the shortened ether tether
of 15b did not affect the DAT binding affinity when
compared to ethyl homologue 3b. The analogues 3b
and 15 were found to be equipotent in both DAT and
SERT binding affinity as well as for inhibition of dopa-
mine uptake. Generally, all of the compounds tested in
this group exhibited modest selectivity for the DAT over
the SERT with a SERT/DAT Ki ratio similar to or less
than that previously reported for GBR 12909. This is
consistent with the SAR of the tropane-GBR hybrids

7948
S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
4. Experimental
removed by filtration through a pad of Celite. The sol-
vent was removed under reduced pressure and the resi-
due was purified by chromatography using a short
column of silica gel (EtOAc).
All chemicals were purchased from Aldrich Chemical
Co., Milwaukee, WI, unless otherwise noted. Anhy-
drous solvents acetonitrile (J. T. Baker), diethyl ether
(VWR), methanol (J. T. Baker), tetrahydrofuran (J. T.
Baker), and toluene (VWR) were used under argon
without further purification. Chromatography refers to
column chromatography on silica gel (Silica Gel 60,
230–400 mesh). Petroleum ether (VWR) refers to pen-
tanes with a boiling point range of 30–60 ꢁC. Reported
melting points are uncorrected. NMR spectra were
recorded on a Varian-Gemini 400 MHz spectrometer.
Chemical shifts are reported as d values with tetrameth-
ylsilane (TMS), employed as the internal standard. Ele-
mental analyses were obtained from Atlantic Microlabs,
Inc., Norcross, GA.
4.4.1. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]oct-2ene-3-
carboxylic acid methyl ester (7). To a solution of 6
(4.0 g, 22 mmol) and potassium carbonate (150 mg,
1.1 mmol) in toluene (40 mL) was added ethyl chloro-
formate (11 mL, 110 mmol). The solution was heated
to reflux for 24 h. The solvent was removed under re-
duced pressure and the residue was dissolved in water
(50 mL). The aqueous mixture was extracted with
CH2Cl2(3· 50 mL), and the combined organic layers
were dried over Na2SO4. The solvent was removed un-
der reduced pressure and the residue was purified by col-
umn chromatography (EtOAc/hexane, 2:8) to yield 7 as
a colorless oil (5.0 g, 95%). 1H NMR (CDCl3) d 7.16 (br
s, 1H), 4.56–4.47 (m, 2H), 4.17–4.10 (m, 2H), 3.72 (s,
3H), 2.90–2.87 (br s, 2H), 2.21–2.12 (m, 1H), 2.06–1.93
(m, 2H), 1.67–1.58 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3) d 167.1, 142.5, 95.5, 75.6, 75.5,
61.1, 52.8, 51.7, 51.6, 33.7, 28.0, 14.7. Anal. Calcd for
C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C,
59.97; H, 7.15; N, 5.81.
4.1. General method A. Preparation of oxalate salts
All of the final compounds were converted into the oxa-
late salts for biological testing as well as for storage and
handling purposes. The base (50–100 mg) was dissolved
in the minimum amount of Et2O (1–2 mL) and a satu-
rated ethereal solution (10 mL) of oxalic acid (1.1 equiv)
was added. The oxalate salts crystallized and were
washed with Et2O (3· 2 mL) and purified by trituration
with Et2O. Fractional moles of water could not be pre-
vented despite vigorous overnight drying (110 ꢁC) under
vacuum (0.01 mmHg). All compounds were homoge-
neous by TLC (CHCl3/CH3OH/NH4OH, 90:9:1).
4.4.2.
8-Ethoxycarbonyl-3-hydroxymethyl-8-azabicy-
clo[3.2.1]oct-2-ene (8). To a stirred solution of lithium
aluminum hydride (711 mg, 18.7 mmol) in THF
(60 mL) was added a solution of 7 (4.3 g, 18 mmol) in
THF (10 mL) dropwise at 0 ꢁC. After the reaction was
complete (TLC), an aqueous solution of potassium
hydroxide (5 mL, 10% wt/wt) was added to quench the
reaction. The mixture was stirred for 30 min at room
temperature. The white precipitate that formed was fil-
tered and rinsed with ethyl acetate. The combined
organic solutions were washed with phosphate buffer
(pH 7, 1 M, 10 mL) and dried over Na2SO4. The solvent
was removed under reduced pressure and the residue
was purified by chromatography (EtOAc/hexane, 1:1)
to yield 8 as a colorless oil (2.4 g, 60%). 1H NMR
(CDCl3) d 5.99 (d, J = 5.2 Hz, 1H), 4.43 (t, J = 5.6,
2H), 3.99–3.91 (m, 2H), 2.71 (d, J = 15.2 Hz, 1H),
2.22–2.14 (m, 2H), 2.06–1.81 (m, 5H), 1.67–1.49 (m,
2H), 1.28–1.23 (m, 2H). 13C NMR (CDCl3) d 154.3,
135.2, 126.8, 67.6, 60.8, 52.3, 34.8, 31.9, 29.6, 14.6,
14.1. Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11;
N, 6.63. Found: C, 61.34; H, 8.08; N, 6.47.
4.2. General procedure B. Decarbonylation
To a stirred solution of the corresponding carbamate
(2.7 mmol) and potassium hydroxide (3.9 g, 70 mmol)
in ethylene glycol (40 mL) was added hydrazine hydrate
(1.3 mL, 27 mmol). The mixture was heated to reflux for
3 h. The reaction mixture was poured into water and
extracted with ether (3· 100 mL). The combined organic
layers were dried over Na2SO4 and the solvent was re-
moved under reduced pressure. The residue was purified
by chromatography (EtOAc/CH3OH/NEt3, 80:8:4).
4.3. General procedure C. N-Arylalkylation of secondary
amines
To a stirred solution of potassium carbonate (230 mg,
1.6 mmol) and secondary amine (0.60 mmol) in DMF
(5 mL) was added either benzyl bromide or 1-bromo-
3-phenylpropane (0.80 mmol) and the mixture was stir-
red at 80 ꢁC for 24 h. The solvent was removed under re-
duced pressure and the residue was dissolved in CH2Cl2
(50 mL). The organic solution was washed with water
(50 mL) and dried over Na2SO4. The solvent was re-
moved under reduced pressure and the residue was puri-
fied by chromatography (EtOAc).
4.4.3.
8-Ethoxycarbonyl-3-diphenylmethoxymethyl-8-
azabicyclo[3.2.1]oct-2-ene (9a). Benzhydryl chloride
(970 mg, 4.8 mmol) was added to 8 (710 mg, 3.2 mmol)
and heated under nitrogen at 160 ꢁC neat for 2 h. The
reaction mixture was allowed to cool to room tempera-
ture and the residue was purified by chromatography
(EtOAc/hexane, 2:8) to yield 9a as a colorless oil
1
(1.5 g, 87%). H NMR (CDCl3) d 7.26–7.19 (m, 8H),
7.18–7.16 (m, 2H), 5.14 (d, J = 2.4 Hz, 1H), 5.26 (s,
1H), 4.36 (br s, 2H), 4.06 (q, J = 6.4 Hz, 2H), 3.75 (s,
2H), 2.66 (br s, 1H), 2.11–2.08 (m, 1H), 1.92–1.81 (m,
4H), 1.17 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3) d
154.3, 142.2, 142.1, 128.5, 128.4, 128.3, 127.7, 127.4,
127.0, 126.9, 126.5, 83.5, 82.0, 71.4, 61.0, 60.9, 52.4,
4.4. General procedure D. Hydrogenation
A solution of the tropene (0.2 mmol), 10% Pd/C (14 mg)
in CH3OH (10 mL) was hydrogenated at 55 psi for 24 h
on Parr hydrogenation apparatus. The solids were then

S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
7949
35.1, 29.0, 14.6. Anal. Calcd for C24H27NO3: C, 76.36;
H, 7.21; N, 3.71. Found: C, 75.99; H, 7.28; N, 3.74.
(210 mg, 80%). 1H NMR (CDCl3) d 7.36–7.22 (m,
10H), 7.04–6.99 (m, 3H), 5.77 (d, J = 5.6 Hz, 1H), 5.36
(s, 1H), 3.84 (ABq, JAB = 12.4 Hz, Dm = 18.2 Hz, 2H),
3.70–3.66 (m, 2H), 3.37–3.34 (m, 1H), 3.31–3.28 (m,
1H), 2.55–2.51 (m, 1H), 2.20–2.12 (m, 1H), 2.07–1.98
(m, 1H), 1.86–1.83 (m, 1H), 1.71–1.67(m, 1H), 1.56–
1.49 (m, 1H). 13C NMR (CDCl3) d 163.3, 160.9, 139.5,
138.0, 137.8, 131.6, 128.7, 128.6, 128.5, 128.5, 128.2,
128.1, 126.9, 126.8, 115.4, 115.3, 115.3, 115.2, 115.1,
80.6, 71.8, 56.4, 55.4, 53.1, 33.8, 32.5, 29.7. Anal. Calcd
for C28H27F2NOÆC2H2O4Æ1/2H2O: C, 67.95; H, 5.69; N,
2.68. Found: C, 67.58; H, 5.65; N, 2.64.
4.4.4. 8-Ethoxycarbonyl-3-di(4-fluorophenyl)methoxym-
ethyl-8-azabicyclo[3.2. 1]oct-2-ene (9b). Bis(4-fluorophe-
nyl)chloromethane (1.1 g, 4.8 mmol) was added to 8
(710 mg, 3.2 mmol) and heated under nitrogen at
160 ꢁC neat for 2 h. The reaction mixture was allowed
to cool to room temperature and the residue was purified
by chromatography (EtOAc/hexane, 2:8) to yield 9b as a
colorless oil (1.6 g, 80%). 1H NMR (CDCl3) d 7.34–7.23
(m, 4H), 7.05–6.98 (m, 4H), 5.96 (d, J = 3.6 Hz, 1H), 5.27
(s, 1H), 4.42 (br s, 2H), 4.15–4.08 (m, 2H), 3.77 (s, 2H),
2.66 (br s, 1H), 2.18–2.10 (m, 1H), 2.05–1.83 (m, 2H),
1.68–1.58 (m, 2H), 1.28–1.21 (m, 3H). 13C NMR
(CDCl3) d 163.5, 163.4, 161.0, 154.4, 137.7, 128.6,
128.5, 128.2, 128.1, 115.5, 115.4, 115.3, 115.2, 74.9,
71.5, 61.0, 60.9, 52.8, 51.9, 35.1, 29.4, 14.7. Anal. Calcd
for C24H25 F2NO3ÆH2O: C, 66.81; H, 6.31; N, 3.25.
Found: C, 66.23; H, 5.70; N, 3.22.
4.4.9. 3-(Diphenylmethoxymethyl)-8-(3-phenylpropyl)-8-
azabicyclo[3.2.1]oct-2-ene (12a). General procedure C.
The compound was obtained as a light yellow oil
(220 mg, 87%). 1H NMR (CDCl3) d 7.33–7.14 (m,
15H), 5.76 (d, J = 4.8 Hz, 1H), 5.35 (s, 1H), 3.82
(ABq, JAB = 12.0 Hz, Dm = 17.2 Hz, 2H), 3.40–3.39 (m,
2H), 2.63 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H),
2.46–2.42 (m, 1H), 2.15–2.10 (m, 1H), 2.04–2.00 (m,
1H), 1.91–1.81 (m, 4H), 1.72–1.68 (m, 1H), 1.55–1.48
(m, 1H). 13C NMR (CDCl3) d 142.4, 142.2, 131.9,
128.3, 128.2, 127.4, 127.0, 126.9, 125.7, 82.0, 71.6,
56.8, 55.6, 48.4, 33.9, 33.7, 62.2, 30.3, 29.5. Anal. Calcd
for C30H33NOÆC2H2O4: C, 74.83; H, 6.87; N, 2.73.
Found: C, 74.19; H, 6.82; N, 2.73.
4.4.5. 3-Diphenylmethoxymethyl-8-azabicyclo[3.2.1]oct-
2ene (10a). General procedure B. The compound was ob-
1
tained as a light yellow oil (580 mg, 71%). H NMR
(CDCl3) d 7.28–7.23 (m, 8H), 7.20–7.16 (m, 2H), 5.90
(d, J = 5.2 Hz, 1H), 5.28 (s, 1H), 3.83–3.82 (m, 1H),
3.59 (s, 2H), 3.03 (br s, 2H), 2.48 (m, 1H), 1.98–1.77
(m, 4H), 1.52–1.49 (m, 1H). 13C NMR (CDCl3) d
142.2, 142.1, 131.5, 130.7, 128.3, 127.4, 127.3, 126.9,
126.8, 82.2, 71.8, 63.4, 53.1, 52.5, 36.8, 35.2, 29.8. Anal.
Calcd for C21H23NOÆ1/2H2O: C, 80.22; H, 7.69; N, 4.45.
Found: C, 80.01; H, 7.63; N, 4.49.
4.4.10. 3-Di(4-fluorophenyl)methoxymethyl-8-(3-phenyl-
propyl)-8-azabicyclo[3.2.1]oct-2-ene (12b). General proce-
dure C. The compound was obtained as a light yellow oil
1
(223 mg, 81%). H NMR (CDCl3) d 7.28–7.18 (m, 4H),
7.16–7.14 (m, 5H), 7.03–6.98 (m, 4H), 5.75 (d,
J = 4.8 Hz, 1H), 5.30 (s, 1H), 3.78 (ABq, JAB = 12.0 Hz,
Dm = 17.2 Hz, 2H), 3.41 (br s, 2H), 2.64 (t, J = 7.2 Hz,
2H), 2.53 (t, J = 15.2 Hz, 2H), 2.46–2.42 (m, 1H),
2.16–2.14 (m, 1H), 2.05–2.02 (m, 2H), 1.90–1.81 (m,
2H), 1.70–1.66 (m, 1H), 1.55–1.48 (m, 1H). 13C NMR
(CDCl3) d 163.4, 161.0, 155.2, 138.0, 131.8, 128.7,
128.6, 128.6, 128.5, 128.4, 128.3, 125.8, 115.5, 115.4,
115.3, 115.2, 80.7, 75.6, 75.5, 71.6, 60.4, 56.9, 55.7,
48.5, 33.9, 33.6, 32.4, 30.2, 29.5, 14.2. Anal. Calcd for
C30H31F2NOÆC2H2O4: C, 69.93; H, 6.05; N, 2.55.
Found: C, 69.65; H, 6.08; N, 2.48.
4.4.6.
3-Di(4-fluorophenyl)methoxymethyl-8-azabicy-
clo[3.2.1]oct-2-ene (10b). General procedure B. The
compound was obtained as a light yellow oil (650 mg,
70%). 1H NMR (CDCl3) d 7.29–7.25 (m, 4H), 7.03–6.98
(m, 4H), 5.45 (d, J = 5.2 Hz, 1H), 5.31 (s, 1H), 3.78–
3.74 (m, 2H), 3.70 (s, 2H), 2.50 (br s, 2H), 1.96–1.83 (m,
4H), 1.60–1.26 (m, 1H). 13C NMR (CDCl3) d 163.4,
161.0, 160.9, 138.0, 137.9, 137.8, 137.7, 131.4, 130.9,
128.7, 128.6, 128.5, 115.5, 115.2, 80.8, 71.8, 63.6, 53.2,
36.9, 30.0, 14.2. Anal. Calcd for C21H21F2NO: C, 73.88;
H, 6.20; N, 4.10. Found: C, 73.93; H, 6.50; N, 4.23.
4.4.7.
8-Benzyl-3-diphenylmethoxymethyl-8-azabicy-
4.4.11.
8-Methyl-3-diphenylmethoxymethyl-8-azabicy-
clo[3.2.1]oct-2-ene (11a). General procedure C. The com-
pound was obtained as a light yellow oil (208 mg, 81%).
1H NMR (CDCl3) d 7.39–7.23 (m, 15H), 5.78 (d,
J = 5.2 Hz, 1H), 5.40 (s, 1H), 3.89 (ABq, JAB = 12.4 Hz,
Dm = 18.0 Hz, 2H), 3.74–3.70 (m, 2H), 3.39 (br s, 1H),
3.33–3.30 (m, 1H), 2.56 (d, J = 17.2 Hz, 1H), 2.20–2.16
(m, 1H), 2.04–2.00 (m, 1H), 1.83 (t, J = 10.8 Hz, 1H),
1.72 (m, 1H), 1.59–1.52 (m, 1H). 13C NMR (CDCl3) d
142.4, 142.2, 141.1, 139.2, 128.9, 128.5, 128.4, 128.2,
127.8, 127.7, 127.5, 127.4, 127.3, 127.0, 126.9, 82.0,
71.7, 56.3, 55.5, 33.8, 32.3, 29.7. Anal. Calcd for
C28H29NOÆC2H2O4Æ1/2H2O: C, 72.21; H, 6.52; N, 2.83.
Found: C, 72.13; H, 6.47; N, 2.76.
clo[3.2.1]oct-2-ene (13a). To a stirred solution of 10a
(150 mg, 0.5 mmol) and 37% aqueous formaldehyde
(0.2 mL, 2.5 mmol) in acetonitrile (10 mL) under nitro-
gen was added sodium cyanoborohydride (49 mg,
0.7 mmol). The reaction mixture was stirred for
10 min, and then glacial acetic acid was added dropwise
until the solution was neutral (pH 7). Stirring was then
continued for an additional 45 min, then saturated sodi-
um bicarbonate solution was added until the solution
was of pH 9. The acetonitrile was evaporated and the
resulting solution was extracted with CHCl3 (3·
50 mL). The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by chromatography
(EtOAc/CH3OH/Et3N, 40:2:1) to yield 13a as a light yel-
4.4.8. 8-Benzyl-3-di(4-fluorophenyl)methoxymethyl-8-
azabicyclo[3.2.1]oct-2-ene (11b). General procedure C.
The compound was obtained as a light yellow oil
1
low oil (127 mg, 81%). H NMR (CDCl3) d 7.28–7.19
(m, 10H), 5.72 (d, J = 8.0 Hz, 1H), 5.29 (s, 1H), 3.77

7950
S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
(ABq, JAB = 8.0 Hz, Dm = 16.0 Hz, 2H), 3.19 (m, 2H),
2.42 (d, J = 8.0 Hz, 1H), 2.29 (s, 3H), 2.14–1.95 (m,
2H), 1.79–1.77 (m, 1H), 1.62–1.60 (m, 1H), 1.51–1.48
(m, 1H). 13C NMR (CDCl3) d 142.4, 142.2, 131.4,
128.3, 127.7, 127.4, 127.3, 127.0, 126.9, 82.0, 71.7,
58.8, 57.6, 33.7, 29.7. Anal. Calcd for C22H25NOÆ-
C2H2O4: C, 70.40; H, 6.65; N, 3.42. Found: C, 69.54;
H, 6.65; N, 3.47.
4.4.15. 3a-Diphenylmethoxymethyl-8-(3-phenylpropyl)-8-
azabicyclo[3.2.1]octane (15a). General procedure D. The
compound was obtained as a colorless oil (78 mg,
1
92%). H NMR (CDCl3) d 7.35–7.17 (m, 15H), 5.32 (s,
1H), 3.40 (d, J = 8.0 Hz, 2H), 3.20 (br s, 2H), 2.65 (t,
J = 7.2 Hz, 2H), 2.41 (br s, 2H), 2.08–2.14 (m, 3H),
1.86 (br s, 4H), 1.50–1.47 (m, 2H), 1.37 (d, J = 8.4 Hz,
2H). 13C NMR (CDCl3) d 142.3, 142.0, 128.1, 128.0,
127.4, 127.9, 127.1, 126.7, 125.4, 83.1, 74.2, 60.0, 57.9,
50.9, 33.6, 31.4, 30.3, 28.2, 26.6, 20.7, 14.0. Anal. Calcd
for C30H35NOÆC2H2O4: C, 74.54; H, 7.23; N, 2.72.
Found: C, 74.03; H, 7.28; N, 2.67.
4.4.12. 3-Di(4-fluorophenyl)methoxymethyl-8-methyl-8-
azabicyclo[3.2.1]oct-2-ene (13b). To a stirred solution
of 10b (260 mg, 0.8 mmol) and 37% aqueous formalde-
hyde (0.3 mL, 3.8 mmol) in acetonitrile (10 mL) under
nitrogen was added sodium cyanoborohydride (76 mg,
1.1 mmol). The reaction mixture was stirred for
10 min, and then glacial acetic acid was added dropwise
until the solution was neutral (pH 7). Stirring was then
continued for an additional 45 min, then saturated sodi-
um bicarbonate solution was added until the solution
was of pH 9. The acetonitrile was evaporated and the
resulting solution was extracted with CHCl3 (3·
50 mL). The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by chromatography
(EtOAc/CH3OH/Et3N, 40:2:1) to yield 13b as a light
4.4.16. 3a-Di(4-fluorophenyl)methoxymethyl-8-(3-phenyl-
propyl)-8-azabicyclo[3.2.1]octane (15b). General proce-
dure D. The compound was obtained as a colorless oil
1
(83 mg, 90%). H NMR (CDCl3) d 7.28–7.24 (m, 6H),
7.18–7.17 (m, 3H), 7.01–6.97 (m, 4H), 5.27 (s, 1H),
3.59 (d, J = 8.0 Hz, 2H), 3.16 (d, J = 8.0 Hz, 2H),
2.91–2.85 (m, 1H), 2.64 (t, J = 7.6 Hz, 2H), 2.36 (t,
J = 7.2 Hz, 2H), 2.14–2.12 (m, 4H), 1.87–1.79 (m, 4H),
1.44–1.41 (m, 1H), 1.32 (d, J = 8.0 Hz, 1H). 13C NMR
(CDCl3) d 163.2, 160.7, 142.1, 138.0,137.9, 128.5,
128.4, 128.2, 128.1, 126.9, 125.5, 115.2, 115.0, 81.9,
74.3, 60.2, 58.0, 51.1, 36.3, 33.6, 31.5, 30.3, 28.3, 26.7,
20.9, 14.0. Anal. Calcd for C30H33F2NOÆC2H2O4: C,
69.68; H, 6.40; N, 2.54. Found: C, 69.20; H, 6.45; N,
2.57.
1
yellow oil (218 mg, 81%). H NMR (CDCl3) d 7.28–
7.25 (m, 4H), 7.02–6.98 (m, 4H), 5.79 (d, J = 8.0 Hz,
1H), 5.31 (s, 1H), 3.82 (ABq, JAB = 12.0 Hz,
Dm = 17.4 Hz, 2H), 3.28–3.26 (m, 2H), 2.58–2.56 (m,
1H), 2.35 (s, 3H), 2.23–2.17 (m, 2H), 1.97–1.90 (m,
1H), 1.80–1.76 (m, 1H), 1.58 (br s, 1H). 13C NMR
(CDCl3) d 163.4, 160.9, 138.0, 137.8, 131.2, 128.7,
128.6, 128.5, 128.4, 128.0, 115.4, 115.2, 80.6, 71.6,
58.9, 57.6, 33.6, 29.5. Anal. Calcd for C22H23F2NOÆ-
C2H2O4: C, 64.71; H, 5.66; N, 3.14. Found: C, 62.39;
H, 5.67; N, 3.19.
4.4.17. 8-Methyl-3a-diphenylmethoxymethyl-8-azabicy-
clo[3.2.1]octane (16a). General procedure D. The
compound was obtained as a colorless oil (64 mg,
1
99%). H NMR (CDCl3) d 7.35–7.24 (m, 10H), 5.33 (s,
1H), 3.41 (d, J = 7.2 Hz, 2H), 3.15 (br s, 2H), 2.32 (s,
3H), 2.19–2.17 (m, 3H), 2.00–1.97 (m, 2H), 1.57–1.54
(m, 2H), 1.44–1.41 (m, 2H). 13C NMR (CDCl3) d
142.5, 128.2, 127.3, 127.0, 83.3, 74.3, 60.2, 40.0, 32.1,
28.0, 26.3. Anal. Calcd for C22H27NOÆC2H2O4: C,
70.05; H, 7.10; N, 3.40. Found: C, 69.58; H, 7.07; N, 3.34.
4.4.13. 8-Benzyl-3a-(diphenylmethoxy)methyl-8-azabicy-
clo[3.2.1]octane (14a). General procedure D. The
compound was obtained as a light yellow oil (81 mg,
1
91%). H NMR (CDCl3) d 7.38–7.21 (m, 15H), 5.23 (s,
4.4.18. 8-Methyl-3b-di(4-fluorophenyl)methoxymethyl-8-
azabicyclo[3.2.1]octane (16b). General procedure D. The
compound was obtained as a colorless oil (64 mg, 90%).
1H NMR (CDCl3) d 7.28–7.25 (m, 4H), 7.02–6.98 (m,
4H), 5.28 (s, 1H), 3.37 (d, J = 8.4 Hz, 2H), 3.20 (br s,
2H), 2.35 (s, 3H), 2.28–2.22 (m, 3H), 2.04–1.97 (m, 2H),
1.55–1.52 (m, 2H), 1.42 (d, J = 8.4 Hz, 2H). 13C NMR
(CDCl3) d 163.3, 160.9, 138.0, 137.9, 115.4, 115.2, 82.0,
73.8, 60.6, 40.0, 31.5, 27.6, 26.0. Anal. Calcd for
C22H25F2NOÆC2H2O4: C, 64.42; H, 6.08; N, 3.13. Found:
C, 63.86; H, 6.12; N, 3.07.
1H), 3.54 (s, 2H), 3.41 (d, J = 8.0 Hz, 2H), 3.12 (br s,
2H), 2.18 (t, J = 8.4 Hz, 1H), 2.11–2.05 (m, 2H), 1.97–
1.94 (m, 2H), 1.47–1.36 (m, 4H). 13C NMR (CDCl3) d
142.6, 142.4, 140.0, 132.4, 130.1, 128.6, 128.5, 128.4,
128.3, 128.2, 128.1, 127.5, 127.4, 127.3, 127.0, 126.9,
126.6, 126.5, 83.4, 74.5, 58.9, 58.1, 56.3, 32.5, 29.7,
29.4, 29.3, 28.6, 27.0, 26.7. Anal. Calcd for C28H31NOÆ
C2H2O4Æ2H2O: C, 68.89; H, 7.50; N, 2.67. Found: C,
68.00; H, 6.80; N, 2.47.
4.4.14. 8-Benzyl-3a-di(4-fluorophenyl)methoxymethyl-8-
azabicyclo[3.2.1]octane (14b). From 17 general proce-
dure C. The compound was obtained as a colorless oil
(226 mg, 87%). 1H NMR (CDCl3) d 7.40–7.38 (m,
2H), 7.33–7.24 (m, 7H), 7.03–6.98 (m, 4H), 5.28 (s,
1H), 3.55 (s, 2H), 3.38 (d, J = 7.2 Hz, 2H), 3.16 (br s,
2H), 2.20–2.13 (m, 3H), 2.00–1.98 (m, 2H), 1.45–1.37
(m, 4H). 13C NMR (CDCl3) d 163.4, 160.9, 138.1,
128.6, 128.5, 128.2, 115.4, 115.1, 82.1, 75.6, 74.3, 58.1,
56.1, 32.3, 28.4, 26.9. Anal. Calcd for C28H29F2NOÆ-
C2H2O4Æ3/2H2O: C, 65.68; H, 6.25; N, 2.55. Found: C,
65.67; H, 6.07; N, 2.55.
4.4.19. 3a-Di(4-fluorophenyl)methoxymethyl-8-azabicy-
clo[3.2.1]octane (17). General procedure D. The com-
pound was obtained as a colorless oil (62 mg, 90%).
1H NMR (CDCl3) d 7.29–7.25 (m, 4H), 7.03–6.98 (m,
4H), 5.29 (S, 1H), 3.59 (br s, 1H), 3.47 (s, 1H), 3.39
(d, J = 8.0 Hz, 2H), 2.22–2.08 (m, 1H), 1.97–1.86 (m,
4H), 1.58–1.47 (m, 4H). 13C NMR (CDCl3) d 163.4,
160.9, 137.9, 128.6, 128.5, 115.4, 115.2, 82.1, 73.5,
53.5, 32.4, 29.6, 28.4. Anal. Calcd for C21H23F2NO: C,
73.45; H, 6.75; N, 4.08. Found: C, 73.21; H, 6.56; N,
4.18.

S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
7951
4.4.20. 3b-Hydroxymethyl-8-methyl-8-azabicy-
clo[3.2.1]octane (19). To a mixture of powdered lithium
aluminum hydride (1.9 g, 49 mmol) and solid 18 (2.1 g,
12 mmol) at À78 ꢁC, THF (80 mL) was added dropwise.
The mixture was stirred at À78 ꢁC for 8 h then allowed
to slowly warm to room temperature overnight. An
aqueous solution of potassium hydroxide (10 mL, 10%
wt/wt) was added to quench the reaction. The mixture
was stirred for 30 min at room temperature. The white
precipitate was filtered and rinsed with EtOAc. The
combined organic solutions were dried over Na2SO4
and the solvent was removed under reduced pressure
to yield 19 as a colorless oil that was used in subsequent
reactions without purification.
1H), 3.39 (d, J = 8.0 Hz, 2H), 2.22–2.08 (m, 1H), 1.97–
1.86 (m, 4H), 1.58–1.47 (m, 4H). 13C NMR (CDCl3) d
163.1, 160.7, 138.0, 137.9, 128.3, 128.2, 115.1, 115.0,
82.1, 74.4, 63.0, 54.1, 36.4, 29.4, 29.0. Anal. Calcd for
C21H23F2NO: C, 73.45; H, 6.75; N, 4.08. Found: C,
73.21; H, 6.56; N, 4.18.
4.4.25. 8-Benzyl-3b-diphenylmethoxymethyl-8-azabicy-
clo[3.2.1]octane (22a). General procedure D. The com-
pound was obtained as a colorless oil (60 mg, 76%).
1H NMR (CDCl3) d 7.38–7.20 (m, 15H), 5.28 (s, 1H),
3.54 (s, 2H), 3.27 (d, J = 6.8 Hz, 2H), 3.20 (br s, 2H),
2.04–1.99 (m, 4H), 1.63–1.53 (m, 4H), 1.50–1.47 (m,
1H). 13C NMR (CDCl3) d 142.5, 128.3, 128.1, 127.3,
126.9, 126.7, 83.7, 74.7, 58.8, 56.3, 34.9, 29.2, 26.6. Anal.
Calcd for C28H31NOÆC2H2O4ÆH2O: C, 71.26; H, 6.97; N,
2.77. Found: C, 70.77; H, 6.74; N, 2.76.
4.4.21. 8-Methyl-3b-diphenylmethoxymethyl-8-azabicy-
clo[3.2.1]octane (20a). Benzhydryl chloride (2.0 g,
9.9 mmol) was added to 19 (1.0 g, 6.4 mmol) and heated
under nitrogen at 150 ꢁC neat for 2 h. The reaction mix-
ture was allowed to cool to room temperature and the
residue was purified by chromatography (EtOAc/
CH3OH/NEt3, 80:8:4) to yield 20a as a colorless oil
4.4.26. 8-Benzyl-3b-di(4-fluorophenyl)methoxymethyl-8-
azabicyclo[3.2.1]octane (22b). General procedure D. The
compound was obtained as a colorless oil (66 mg,
76%). 1H NMR (CDCl3) d 7.37–7.34 (m, 3H), 7.31–
7.22 (m, 7H), 7.01–6.97 (m, 3H), 5.24 (s, 1H), 3.53 (s,
2H), 3.28 (d, J = 6.4 Hz, 2H), 3.20 (br s, 2H), 2.05–
1.99 (m, 4H), 11.62–1.51 (m, 4H), 1.46–1.25 (m, 2H).
13C NMR (CDCl3) d 163.3, 160.9, 138.2, 138.1, 128.6,
128.5, 128.4, 128.1, 126.9, 115.3, 115.1, 82.4, 74.7,
58.8, 56.4, 35.1, 29.2, 26.6. Anal. Calcd for
C28H29F2NOÆC2H2O4: C, 68.82; H, 5.97; N, 2.68.
Found: C, 68.27; H, 6.10; N, 2.57.
1
(1.2 g, 60%). H NMR (CDCl3) d 7.33–7.22 (m, 10H),
5.28 (s, 1H), 3.25 (d, J = 6.8 Hz, 2H), 3.16 (br s, 2H),
2.26 (s, 3H), 2.02–1.99 (m, 4H), 1.62–1.57 (m, 4H),
1.57–1.54 (m, 2H), 1.49–1.45 (m, 1H). 13C NMR
(CDCl3) d 142.5, 128.3, 127.3, 126.9, 83.7, 74.5, 61.0,
40.1, 34.9, 28.5, 26.1. Anal. Calcd for C22H27NOÆ-
C2H2O4: C, 70.05; H, 7.10; N, 3.40. Found: C, 69.97;
H, 7.23; N, 3.52.
4.4.22. 3b-Di(4-fluorophenyl)methoxymethyl-8-methyl-8-
azabicyclo[3.2.1]octane (20b). Chloro-bis(4-fluorophe-
nyl)methane (2.3 g, 9.5 mmol) was added to 19 (1.0 g,
6.4 mmol) and heated under nitrogen at 150 ꢁC neat
for 2 h. The reaction mixture was allowed to cool to
room temperature and the residue was purified by chro-
matography (EtOAc/CH3OH/NEt3, 80:8:4) to yield 20b
as a colorless oil (1.5 g, 67%). 1H NMR (CDCl3) d 7.28–
7.25 (m, 4H), 7.02–6.98 (m, 4H), 5.25 (s, 1H), 3.26 (d,
J = 6.8 Hz, 2H), 3.15 (br s, 2H), 2.26 (s, 3H), 2.02–
1.99 (m, 4H), 1.59–1.56 (m, 4H), 1.43–1.39 (m, 1H).
13C NMR (CDCl3) d 163.2, 160.8, 138.0, 128.4, 128.3,
115.2, 115.0, 82.3, 74.5, 60.9, 40.3, 35.1, 28.5, 26.0. Anal.
Calcd for C22H25F2NOÆHClÆ1/2H2O: C, 65.70; H, 6.75;
N, 3.48. Found: C, 65.44; H, 6.70; N, 3.38.
4.4.27. 3b-Diphenylmethoxymethyl-8-(3-phenylpropyl)-8-
azabicyclo[3.2.1]octane (23a). General procedure D. The
compound was obtained as a colorless oil (65 mg, 77%).
1H NMR (CDCl3) d 7.32–7.16 (m, 15H), 5.28 (s, 1H),
3.33 (d, J = 8.0 Hz, 2H), 3.25 (d, J = 6.0 Hz, 2H), 2.63
(t, J = 8.0 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.05–2.03
(m, 2H), 1.95–1.85 (m, 4H), 1.62–1.54 (m, 5H). 13C
NMR (CDCl3) d 142.4, 141.8, 128.3, 128.2, 127.3,
126.8, 125.7, 83.7, 75.5, 74.2, 60.3, 58.9, 50.8, 33.6, 29.5,
28.8, 26.3. Anal. Calcd for C30H35NOÆC2H2O4: C,
74.54; H, 7.23; N, 2.72. Found: C, 73.21; H, 7.14; N, 2.65.
4.4.28. 3b-Di(4-fluorophenyl)methoxymethyl-8-(3-phenyl-
propyl)-8-azabicyclo[3.2.1]octane (23b). General proce-
dure D. The compound was obtained as a colorless oil
1
(72 mg, 78%). H NMR (CDCl3) d 7.28–7.23 (m, 6H),
4.4.23. 3b-Diphenylmethoxymethyl-8-azabicyclo[3.2.1]oc-
tane (21a). General procedure B. The compound was ob-
tained as a light yellow oil (630 mg, 77%). H NMR
(CDCl3) d 7.33–7.27 (m, 8H), 7.25–7.20 (m, 2H), 5.27
(s, 1H), 3.62 (s, 1H), 3.24 (d, J = 6.4 Hz, 2H), 3.08 (br
s, 2H), 2.12–2.03 (m, 1H), 1.82–1.79 (m, 2H), 1.35–
1.32 (m, 2H). 13C NMR (CDCl3) d 142.4, 128.2, 127.2,
126.8, 83.7, 74.5, 63.2, 54.2, 36.5, 29.5, 29.0. Anal. Calcd
for C21H23NOÆ1/2H2O: C, 79.71; H, 8.28; N, 4.43.
Found: C, 79.90; H, 8.08; N, 4.49.
7.18–7.14 (m, 3H), 7.01–6.97 (m, 4H), 5.23 (s, 1H),
3.24 (br s, 2H), 3.21 (d, J = 6.4 Hz, 2H), 2.63 (t,
J = 11.2 Hz, 2H), 2.37 (t, J = 7.2 Hz, 1H), 2.03–1.96
(m, 2H), 1.91–1.89 (m, 2H), 1.84–1.77 (m, 2H), 1.56–
1.52 (m, 4H), 1.43–1.37 (m, 1H). 13C NMR (CDCl3) d
163.3, 160.9, 142.2, 138.1, 138.0, 128.5, 128.4, 128.3,
128.2, 125.7, 115.3, 115.1, 82.4, 74.5, 58.9, 51.4, 34.4,
33.7, 30.1, 29.0, 26.4. Anal. Calcd for C30H33F2NOÆ-
C2H2O4: C, 69.68; H, 6.40; N, 2.54. Found: C, 69.40;
H, 6.32; N, 2.48.
1
4.4.24. 3b-Di(4-fluorophenyl)methoxymethyl-8-azabicy-
clo[3.2.1]octane (21b). General procedure B. The com-
pound was obtained as a light yellow oil (710 mg,
77%). 1H NMR (CDCl3) d 7.29–7.25 (m, 4H), 7.03–
6.98 (m, 4H), 5.29 (s, 1H), 3.59 (br s, 1H), 3.47 (s,
4.5. [3H]Citalopram binding assay
Brains from male Sprague–Dawley rats weighing 200–
225 g (Taconic Labs) were removed, midbrain dissected
and rapidly frozen. Membranes were prepared by

7952
S. Zhang et al. / Bioorg. Med. Chem. 14 (2006) 7943–7952
12. Choi, S.-W.; Elmaleh, D. R.; Hanson, R. N.; Fischman,
A. J. J. Med. Chem. 1999, 42, 3647–3656.
13. Husbands, S. M.; Izenwasser, S.; Kopajtic, T.; Bowen, W.
D.; Vilner, B. J.; Katz, J. L.; Newman, A. H. J. Med.
Chem. 1999, 42, 4446–4455.
14. Lewis, D. B.; Matecka, D.; Zhang, Y.; Hsin, L. W.;
Dersch, C. M.; Stafford, D.; Glowa, J. R.; Rothman, R.
B.; Rice, K. C. J. Med. Chem. 1999, 42, 5029–5042.
15. Choi, S.-W.; Elmaleh, D. R.; Hanson, R. N.; Fischman,
A. J. J. Med. Chem. 2000, 43, 205–213.
16. Zhang, Y.; Rothman, R. B.; Dersch, C. M.; deCosta, B.
R.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2000, 43,
4840–4849.
17. Dutta, A. K.; Fei, X.-S.; Beardsley, P. M.; Newman, J. L.;
Reith, M. E. A. J. Med. Chem. 2001, 44, 937–948.
18. Prisinzano, T. E.; Greiner, E.; Johnson, E. M., II; Dersch,
C. M.; Marcus, J.; Partilla, J. S.; Rothman, R. B.;
Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2002, 45,
4371–4374.
19. Bradley, A. L.; Izenwasser, S.; Wade, D.; Klein-Stevens,
C.; Zhu, N.; Trudell, M. L. Bioorg. Med. Chem. Lett.
2002, 12, 2387–2390.
homogenizing tissues in 25 vol (w/v) of 50 mM Tris con-
taining 120 mM NaCl and 5 mM KCl (pH 7.4 at 25 ꢁC)
using a Brinkman Polytron (setting 6 for 20 s) and cen-
trifuged at 20,000g for 10 min at 4 ꢁC. The resulting pel-
let was resuspended in buffer, recentrifuged, and
resuspended in buffer to a concentration of 7.5 mg/mL.
Ligand binding experiments were conducted in assay
tubes containing 4.0 mL buffer for 60 min at room tem-
perature. Each tube contained 1.4 nM [3H]citalopram
(GE Healthcare) and 1.5 mg midbrain tissue (original
wet weight). Nonspecific binding was determined using
1 lM citalopram. Incubations were terminated by rapid
filtration through Whatman GF/B filters, presoaked in
0.3% polyethylenimine, using a Brandel R48 filtering
manifold (Brandel Instruments Gaithersburg, Mary-
land). The filters were washed twice with 5 mL cold buff-
er and transferred to scintillation vials. Beckman Ready
Safe (3.0 mL) was added and the vials were counted the
next day using a Beckman 6000 liquid scintillation
counter (Beckman Coulter Instruments, Fullerton, Cal-
ifornia). Data were analyzed by using GraphPad Prism
software (San Diego, California).
20. Ghorai, S. K.; Cook, C.; Davis, M.; Venkatarama, S. K.;
George, C.; Beardsley, P. M.; Reith, M. A. E.; Dutta, A.
K. J. Med. Chem. 2003, 46, 1220–1228.
21. Greiner, E.; Prisinzano, T. E.; Johnson, E. M., II; Dersch,
C. M.; Marcus, J.; Partilla, J. S.; Rothman, R. B.;
Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2003, 46,
1465–1469.
22. Greiner, E.; Boos, T. L.; Prisinzano, T. E.; De Martino,
M. G.; Zeglis, B.; Dersch, C. M.; Marcus, J.; Partilla, J. S.;
Rothman, R. B.; Jacobson, A. E.; Rice, K. C. J. Med.
Chem. 2006, 49, 1766–1772.
Acknowledgment
We are grateful to the National Institute on Drug Abuse
(DA11528) for the financial support of this research.
23. Bradley, A. L.; Izenwasser, S.; Wade, D.; Cararas, S. A.;
Trudell, M. L. Bioorg. Med. Chem. Lett. 2003, 13, 629–
632.
24. Cheng, J.; Moore, Z.; Stevens, E. D.; Trudell, M. L. J.
Org. Chem. 2002, 67, 5433–5436.
25. Newman, A. H.; Kline, R. H.; Allen, A. C.; Izenwasser, S.;
George, C.; Katz, J. L. J. Med. Chem. 1995, 38, 3933–
3940.
26. Rhoden, J.; Bouvet, M.; Izenwasser, S.; Wade, D.;
Lomenzo, S. A.; Trudell, M. L. Bioorg. Med. Chem.
2005, 13, 5623–5634.
27. Holmquist, C. R.; Keverline-Frantz, K. I.; Abraham, P.;
Boja, J. W.; Kuhar, M. J.; Carroll, F. I. J. Med. Chem.
1996, 39, 4139–4141.
28. Carroll, F. I.; Lewin, A. H.; Abraham, P.; Parham, K.;
Boja, J. W.; Kuhar, M. J. J. Med. Chem. 1991, 34, 883–
886.
References and notes
1. Substance Abuse and Mental Health Services Adminis-
tration National Household Survey on Drug Abuse: Main
Findings 2001, Department of Health and Human Services:
Washington DC, 2002.
2. Carroll, F. I. J. Med. Chem. 2003, 46, 1775–1794.
3. Dutta, A. K.; Zhang, S.; Kolhatkar, R.; Reith, M. E. A.
Eur. J. Pharmacol. 2003, 479, 93–106.
4. Singh, S. Chem. Rev. 2000, 100, 925–1024.
5. van der Zee, P.; Koger, H. S.; Gootjes, J.; Hespe, W. Eur.
J. Med. Chem. 1980, 15, 363–370.
6. Andersen, P. H. J. Neurochem. 1987, 48, 1887–1896.
7. Andersen, P. H. Eur. J. Pharmacol. 1989, 166, 493–504.
8. Hsin, L. W.; Dersch, C. M.; Baumann, M. H.; Stafford,
D.; Glowa, J. R.; Rothman, R. B.; Jacobson, A. E.; Rice,
K. C. J. Med. Chem. 2002, 45, 1321–1329.
29. Newman, A. H.; Kulkarni, S. S. Med. Res. Rev. 2002, 22,
429–464.
9. Stafford, D.; LeSage, M. G.; Rice, K. C.; Glowa, J. R.
Drug Alc. Depend. 2001, 62, 41–47.
30. Dutta, A. K.; Coffey, L. L.; Reith, M. E. A. J. Med. Chem.
1998, 41, 699–705.
31. Carroll, F. I.; Howell, L. L.; Kuhar, M. J. J. Med. Chem.
1999, 42, 2721–2736.
10. Glowa, J. R.; Fantegrossi, W. E.; Lewis, D. B.; Matecka, D.;
Rice, K. C.; Rothman, R. B. J. Med. Chem. 1996, 39, 4689.
11. Dutta, A. K.; Xu, C.; Reith, M. E. A. J. Med. Chem. 1998,
41, 3293–3297.