Synthesis and biological properties of new 2β-alkyl- and 2β-aryl-3- (substituted phenyl)tropane derivatives: Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters

Article abstract of DOI:10.1021/jm9802564

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further elucidate the nature of cocaine's binding to the dopamine transporter (DAT) through strategic modifications

Full text of DOI:10.1021/jm9802564

J . Med. Chem. 1998, 41, 4973-4982
4973
Syn th esis a n d Biologica l P r op er ties of New 2â-Alk yl- a n d 2â-Ar yl-3-(su bstitu ted
p h en yl)tr op a n e Der iva tives: Ster eoch em ica l Effect of C-3 on Affin ity a n d
Selectivity for Neu r on a l Dop a m in e a n d Ser oton in Tr a n sp or ter s
Alan P. Kozikowski,*,† Gian Luca Araldi,† K. R. C. Prakash,† Mei Zhang,‡ and Kenneth M. J ohnson‡
Drug Discovery Program, Institute of Cognitive and Computational Sciences, Georgetown University Medical Center,
3970 Reservoir Road, N.W., Washington, D.C. 20007-2197, and Department of Pharmacology and Toxicology, University of
Texas Medical Branch, Galveston, Texas 77555-1031
Received April 27, 1998
In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial
agonists, we have been involved in efforts to further elucidate the nature of cocaine’s binding
to the dopamine transporter (DAT) through strategic modifications of its structure. In the
case of the substituent located at the 2-position of the tropane ring, studies have revealed the
ability of the transporter to accommodate groups of diverse structure, including ester, ketone,
alkyl, alkenyl, heterocyclic, and aryl substituents, without loss of DAT binding affinity. In
the present study, we report our results pertaining to the ability of the DAT to accommodate
the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adopt
either a chair or a boat conformation of the tropane ring. Moreover, we discuss the influence
of the stereochemistry of these compounds in their selectivity for the DAT versus the serotonin
transporter (5HTT). Additionally, we point out the importance of using Ki values rather than
IC50 values when making such comparisons of transporter selectivity. One of the most
interesting compounds identified in the present work is a 2,3-diaryltropane 22 in a boat
conformation that is highly selective (69-fold) for the DAT over the 5HTT. The ability to prepare
this compound as well as related structures by our oxidopyridinium betaine-based dipolar
cycloaddition strategy further underscores the versatility of this particular chemical approach
to the preparation of diverse tropane analogues. The use of the optically pure olefin p-tolyl
vinyl sulfoxide as the dipolarophile in this reaction allows access to these novel tropanes in
nonracemic form.
In tr od u ction
high potency in the inhibition of radioligand binding to
the DAT.4 These features include an aromatic ring at
the 3-position in place of cocaine’s benzoate group (the
WIN series of compounds) and the presence of a het-
eroatom (nitrogen or oxygen) in the one-atom bridge.5
In the case of the substituent located at the 2-position
of the tropane ring, studies have revealed the ability of
the transporter to accommodate groups of diverse
structure, including ester, ketone, alkyl, alkenyl, het-
erocyclic, and aryl substituents, without loss of DAT
binding affinity.6 In the present study, we report our
results pertaining to the ability of the DAT to accom-
modate the WIN-type structures possessing alkyl or aryl
groups at the 2-position and which adopt either a chair
or a boat conformation of the tropane ring. Moreover,
we discuss the influence of both the nature of the
2-substituent as well as the stereochemistry of the
3-substituent on the selectivity of these analogues for
the DAT versus the serotonin transporter (5HTT). In
particular, we point out the importance of using Ki
values rather than IC50 values when making such
comparisons of transporter selectivity. Recently it has
been suggested that a “paradigm shift” away from the
purely dopaminergic hypothesis of cocaine abuse should
be considered.7 While cocaine self-administration ap-
pears to be best correlated with its activity at the DAT,
cocaine is, in fact, a more potent inhibitor of the
serotonin transporter than it is of either the dopamine
Cocaine is a natural product, produced by Erythroxy-
lum coca, that has been found to cause diverse physi-
ological effects in the mammalian central nervous
system through its action on different neurotransmitter
systems including serotonin (5HT), norepinephrine
(NE), and dopamine (DA).1 Considerable evidence ex-
ists to support the idea that cocaine abuse in humans
is related to its binding to the dopamine transporter
(DAT) in the nucleus accumbens, a region of the
striatum that is implicated in the control of motivation
and reward.2 This action of cocaine leads to an increase
in extracellular DA which is responsible for a potentia-
tion of dopaminergic neurotransmission in the mesolim-
bocortical pathways that are thought to underlie the
reinforcing effects of cocaine.
In pursuit of possible medications, we have been
involved in efforts to further elaborate the nature of
cocaine binding through strategic modifications of its
structure. Such an approach appears promising as we
have already identified several compounds to date that
do not result in full generalization in animal drug
discrimination models.3 Extensive structure-activity
relationship studies of cocaine by a number of groups
have identified certain structural features required for
† Georgetown University Medical Center.
‡ University of Texas Medical Branch.
10.1021/jm9802564 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

4974 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Kozikowski et al.
Sch em e 1a
a
Reagents: (a) LiAlH4, THF, rt; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C; (c) Ph3P+CH2RBr-, n-BuLi, THF, rt; (d) H2 (1 atm), Pd/C,
MeOH.
Sch em e 2a
a
Reagents: (a) p-tolyl vinyl sulfoxide, dioxane, reflux; (b) RMgBr, CuBr‚Me2S, HMPA, TMSCl, THF, -78 °C; (c) LiAlH4, THF, rt; (d)
LiN(i-Pr)2, ClC(S)OPh, THF, -78 °C; (e) Bu3SnH, azobis(isobutyronitrile), toluene, 90 °C; (f) PCl3, DMF, 0 °C; (g) Raney Ni, EtOH, reflux.
or norepinephrine transporters. In fact, current re-
search using DAT knockout mice suggests an important
serotonergic component to the reinforcing effects of
cocaine,8,9 and accordingly issues of transporter selectiv-
ity will remain pivotal to our understanding of cocaine’s
reinforcing effects. As such, a better understanding of
the structural elements relevant to creating small
molecules displaying “tunable” levels of transporter
selectivity may prove valuable to the development of
possible medications. However, at the same time we
do remain mindful of the fact that the creation of a
cocaine medication may actually require the identifica-
tion of a somewhat nonselective drug showing a trans-
porter profile like that of cocaine.
One of the most interesting compounds identified in
the present work is a 2,3-diaryltropane in a boat
conformation that is highly selective for the DAT over
the 5HTT. The ability to prepare this compound as well
as related structures by our oxidopyridinium betaine
strategy further underscores the versatility of this
particular chemical approach to the preparation of
diverse tropane analogues.10
reported in the literature by Clarke et al.11 For com-
pounds 7-10 (Scheme 1), the ester group of the ap-
propriate WIN intermediate was transformed to alde-
hyde by a two-step procedure involving reduction with
LAH and Swern oxidation as previously disclosed by
us.6a Next, Wittig reaction and hydrogenation steps
were carried out to provide the appropriate 2â-alkyl-
3â-aryltropane. While the 2-alkyl-substituted tropanes
reported herein are related to structures reported previ-
ously by us,6a all of the present compounds are new with
the exception of compound 7 which was first described
in ref 6a.
For the synthesis of the tropanes 22-24 which exist
in the boat conformation, we made use of our oxidopy-
ridinium betaine-based dipolar cycloaddition strategy
employing optically pure (R)-(+)-p-tolyl vinyl sulfoxide
as the dipolarophile (Scheme 2).12 The use of this
particular dipolarophile allowed access to the tropanes
in nonracemic form. The copper-catalyzed conjugate
addition reaction of RMgBr to the tropenones 13-15
gave rise to intermediates 16-18 in which introduction
of the proton and the alkyl group occurred from the
â-face. The relative stereochemistry of the substituents
at positions 3 and 4 of these products was confirmed by
observing coupling constants (J 3,4) in the range of 8.4-
9.0 Hz. The magnitudes of these coupling constants are
comparable to those reported previously by us for
products whose structures were confirmed by X-ray
analysis.10 Removal of unwanted ketone and sulfoxide
Ch em istr y
The synthesis of the tropane analogues reported in
this paper was accomplished either by starting from
natural (-)-cocaine or by making use of the oxidopyri-
dinium betaine chemistry reported by us.10 Specifically,
the WIN compounds 1-3 were prepared as originally

Synthesis, Biological Properties of New Tropanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 4975
Sch em e 3a
a
Reagents: (a) NaBH4, CeCl3, MeOH, rt; (b) Ac2O, pyridine, rt; (c) PCl3, DMF, 0 °C; (d) RMgBr, CuCN, ether, rt; (e) Raney Ni (W2),
EtOH, reflux.
groups was then brought about by a series of steps
cases, the ability of some of the tropanes to displace [3H]-
paroxetine binding at the 5HTT has been measured.
involving ketone reduction with LiAH4, Barton-type
deoxygenation of the resulting alcohol, sulfoxide reduc-
tion to sulfide with PCl3, and Raney nickel-promoted
desulfurization. In this manner, access to the twist-
boat tropanes 22-24 was achieved.
Discu ssion
It has previously been noted by Carroll that racemic
2â,3â-diphenyltropane bound the DA transporter with
an IC50 of 28 nM and that this compound has improved
selectivity for DAT over the 5HTT.6b Additionally,
Carroll was the first to report the preparation of a
number of 3R-(4′-substituted phenyl)tropane-2â-car-
boxylic acid methyl esters, existing in a twist-boat
conformation, and to show that these materials are only
1.5-1.9-fold less potent at the DAT than the 2â,3â-
isomers.17 It was also noted by these researchers that
the 2â,3R-isomers were more selective for the DAT over
the 5HTT in comparison to the 2â,3â-isomers. Such
comparisons made use of the observed binding potencies
(IC50’s) at the respective transporters that were mea-
sured by displacement of either [3H]WIN 35428 or [3H]-
paroxetine binding.17
As can be seen from Table 1, in comparing compounds
1 and 2, the effect of the methyl substituent on the
phenyl ring is found to improve binding affinity for the
DAT by about 15-fold, as expected, while having little
effect on the 5HTT/DAT uptake ratio.18 Replacement
of the carbomethoxy group by n-propyl as in the case of
compound 7 leads to both an improvement in binding
affinity in comparison to 1 (7-fold) together with some
improvement in selectivity for the DAT over the 5HTT.
In the case of 35 which exists in the boat conformation,
this compound is comparable in activity to the chair
conformation ester 1, while it is 6-fold less active than
its chair counterpart 7. Interestingly, 35 still retains
its relative selectivity for the DAT over the 5HTT.
Again, as is apparent for compounds 8 and 37, the
appendage of the p-methyl group on the phenyl ring
increases potency about 7-fold for both the chair and
boat structures in comparison to 7 and 35, while the
selectivity for the DAT over the 5HTT is poorer. Similar
effects are observed for the p-fluoro-substituted ana-
logues 10 and 24. The effect of the fluorine atom on
The synthesis of compounds 33-38 from the trope-
none intermediates 13 and 14 was brought about by a
copper-catalyzed cross-coupling reaction (Scheme 3).
Thus, the tropenones 13 and 14 were first subjected to
the Luche reduction to provide the allylic alcohol
intermediates as a mixture of both possible stereoiso-
mers. These alcohols were converted in turn to their
acetates followed by reduction of the sulfoxide to sulfide
using PCl3 in DMF. The sulfides 25 and 26 (3:1 mixture
of the R- and â-acetates) were used directly in the
CuCN-catalyzed cross-coupling reaction with RMgBr (R
) n-Pr, n-Bu, or Ph) to afford 27-31. As reported
previously, this reaction is completely regioselective, and
the final stereochemistry of the newly introduced sub-
stituent is independent of that of the starting acetate.
A W2 Raney nickel-catalyzed hydrogenation/desulfur-
ization reaction then gave access to the final products
as delineated in Scheme 3. The hydrogenation reaction
proceeded with little selectivity from both the R- and
â-faces to afford a chromatographically separable mix-
ture of products.
P h a r m a cology
The tropanes reported herein were examined for their
ability to displace [3H]mazindol binding. Mazindol has
been shown to label the cocaine binding sites on the
dopamine transporter of rat striatal membranes.13 This
ligand binds with high affinity to a single, sodium-
dependent site in striatal membranes, representing the
dopamine carrier. Additionally, these compounds were
tested for their ability to inhibit high-affinity uptake of
[3H]DA and [3H]5HT into striatal nerve endings (syn-
aptosomes).14,15 The protocols used are described in the
Experimental Section. The data are provided in Table
1 along with comparison data for (-)-cocaine. In several

4976 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Kozikowski et al.
Ta ble 1. IC50 and Ki Values for the Tropane Analogues in Mazindol Binding and Dopamine and Serotonin Uptake Experimentsa
mazindol binding (nM)
IC50 Ki
400 281
163 89.4
10.5 5.76
23.1
141
2.97
[3H]DA uptake (nM)
IC50 Ki
459 423
57.9 53.7
7.47 6.92
7.46 6.89
32.6 30.2
1.19 1.10
12.8 11.8
2.16 1.99
13.1 12.1
1.42 1.31
10.9 10.1
[3H]5HT uptake (nM)
uptake ratio
(based on Kis), 5HT/DA
compd
R
R′
isomer
IC50
Ki
cocaine
1
2
7
35
8
37
10
24
9
38
33
36
34
22
23
168
204
155
186
0.37
3.46
3.36
12.6
12.9
9.35
4.25
10.9
8.2
CO2Me
CO2Me Me 2â, 3â
H
2â, 3â
25.5
95.4
427
23.2
86.8
389
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
Ph
H
H
2â, 3â
2â, 3r
12.2
74.9
1.57
Me 2â, 3â
11.3
54.8
23.7
109
16.5
55.8
10.3
50.1
21.7
99.6
15.1
51.0
Me 2â, 3r
18.2
10.0
37.1
8.91
5.28
21.1
1.82
11.4
F
F
2â, 3â
2â, 3r
Me 2â, 3â
3.43
11.5
5.1
Me 2â, 3r
21.6
96.5
26.6
H
H
2â, 3â
2â, 3r
49.9
13.8
31.1
12.6
28.9
11.7
1200
823
80.8
1100
753
73.8
38.1
64.3
25.7
68.9
26.6
Ph
Ph
Ph
Ph
Me 2â, 3â
4.98
5.55
11.4
2.58
2.87
6.00
3.09
2.87
Me 2â, 3r
4.48
4.95
4.16
4.58
314
134
287
122
F
2â, 3r
a
These values represent the mean of 2-3 experiments in which the range of values was not greater than 15%.
Ta ble 2. Comparisons of 5HT/DA Selectivity Ratios Calculated by the Use of IC50 and Ki Values Obtained from Binding and Uptake
Experiments
[3H]mazindol
binding (nM)
[3H]DA
uptake
[3H]paroxetine
binding
[3H]5HT
uptake
binding selectivity
(parox/maz) based on
uptake selectivity
(5HT/DA) based on
compd
IC50
Ki
IC50
57.9
7.47
12.6
4.48
31.1
Ki
IC50
Ki
IC50
204
25.5
823
314
Ki
IC50
s
Kis
IC50
s
Kis
1
2
36
163
10.5
26.6
89.4
53.7
2710
241
7690
3250
135
12.0
410
173
186
23.2
753
287
1100
16.6
22.9
289
1.51
2.07
29.7
60.2
3.52
3.42
65.2
70
38
3.46
3.36
64
69
38
5.76
13.8
2.87
49.9
6.72
11.7
4.16
28.9
22
5.55
586
33
96.5
1200
(()-33a
28a
34700a
1200
a
Data taken from ref 6b in which the binding at the DAT was carried out using WIN 35428 while paroxetine was used for binding at
the 5HTT.
the enhancement of binding affinity is less than that
selectivity for the DAT over the 5HTT, while the boat
compound 36 exhibits a 65-fold selectivity. We will
return to this point shortly, as we believe it is important
to address the means by which transporter selectivity
should be measured.
On comparing compounds 34 and 22, which contain
the p-methyl substituent on the 3-phenyl ring, the
binding affinities improve as expected, with both com-
pounds enjoying comparable potency at the DAT. In
this case, however, 22 shows the best uptake selectivity
of 69-fold for the DAT over the 5HTT. In the case of
the p-fluoro compound 23, only the 2â,3R-isomer was
prepared. As before, the binding potency is less in
comparison to the p-tolyl analogue 22. Also, the uptake
selectivity is poorer.
In Table 2 we provide a comparison of the selectivity
of several of our compounds for the DAT versus the
5HTT. We believe it important to make a point about
evaluating selectivity for various transporters based
upon a comparison of the Ki values versus use of IC50
values. In particular, for the compounds showing the
best selectivity, we note that the use of the IC50 values
based upon binding data leads to suggestions of enor-
mous selectivity differences at the DAT and the 5HTT.
In fact, on using the binding data reported by Carroll
for racemic 2â,3â-diphenyltropane (which corresponds
observed for the methyl substituent.18
The effect of elongating the propyl group to n-butyl
as in the case of 9 and 38 has no real consequences on
activity, as the binding and uptake values obtained are
comparable to those found for compounds 8 and 37.
More exciting activity differences are observed for the
2-phenyl-substituted tropanes. In the case of 33 and
36, a switch in activity is found. The 2â,3R-isomer, the
boat conformer, is more active than its chair counter-
part, the 2â,3â-isomer, by about 4-fold. This is the first
time that such an observation has been made, as the
results reported previously by Carroll concerning such
diaryl-substituted tropanes are only for the chair con-
formers. The chemistry employed by Carroll is limited
to the production of only the 2â,3â- and 2R,3R-isomers,6b
thus revealing another important advantage of the
dipolar cycloaddition strategy developed by us. The
improved binding affinity of 36 over 33 may relate to a
more suitable location of one or both of the aryl
substituents within an appropriate hydrophobic pocket
possibly capable of π-interactions. As one analyzes the
data further, it is evident that the uptake selectivity of
these compounds is also considerably improved over
that of the tropanes bearing alkyl or ester groups at
position 2. The chair compound 33 shows a 38-fold

Synthesis, Biological Properties of New Tropanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 4977
to our compound number 33 and which is accordingly
designated as (()-33 in Table 2), a selectivity of 1200-
fold is suggested.6b This is close to the 586-fold selectiv-
ity calculated for the most DAT-selective tropane of
Table 1, compound 22, based upon the ratio of IC50
values determined from binding. Of course, some
differences are to be expected in the two sets of results
based upon use of WIN 35428 binding in Carroll’s work
and the use of mazindol in our experiments, although
these differences should not be large. A more appropri-
ate comparison of the selectivity of (()-33 would be with
our optically pure 33. However, the selectivity deter-
mined from the ratio of uptake values for 33 is only 38.
Exp er im en ta l Section
Ch em ica l Meth od s. Gen er a l. Starting materials were
obtained from Aldrich Chemical Co. or from other commercial
suppliers. Solvents were purified as follows: diethyl ether was
distilled from phosphorus pentoxide; THF was freshly distilled
under nitrogen from sodium benzophenone.
IR spectra were recorded on an ATI Mattson Genesis
spectrometer. 1H and 13C NMR spectra were obtained with a
Varian Unity Inova instrument at 300 and 75.46 MHz,
respectively. 1H chemical shifts (δ) are reported in ppm
downfield from internal TMS. 13C chemical shifts are refer-
enced to CDCl3 (central peak, δ ) 77.0 ppm), benzene-d6
(central peak, δ ) 128.0 ppm), or DMSO-d6 (central peak, δ )
39.7 ppm). NMR assignments were made with the help of
COSY, DEPT, HETCOR, and NOESY experiments. Melting
points were determined in Pyrex capillaries with a Thomas-
Hoover Unimelt apparatus and are uncorrected. Mass spectra
were measured in the EI mode at an ionization potential of
70 eV. TLC was performed on Merck silica gel 60F254 glass
plates; column chromatography was performed using Merck
silica gel (60-200 mesh). Abbreviations: DMSO, dimethyl
sulfoxide; ether, diethyl ether; THF, tetrahydrofuran; DCM,
dichloromethane.
Compounds 1-3 were prepared from (-)-cocaine by a
procedure analogous that reported in refs 9a and 11.
Meth yl (1R,5S)-3â-p h en yltr op a n e-2â-ca r boxyla te (1):
1H NMR (CDCl3) δ 1.54-1.78 (m, 3H), 2.02-2.24 (m, 2H), 2.23
(s, 3H), 2.60 (dt, 1H, J ) 2.7 and 12.6 Hz), 2.92 (t, 1H, J ) 3.6
Hz), 3.00 (dt, 1H, J ) 5.1 and 12.6 Hz), 3.33-3.42 (m, 1H),
3.48 (s, 3H), 3.52-3.60 (m, 1H), 7.10-7.30 (m, 5H); 13C NMR
(CDCl3) δ 25.2, 25.9, 33.7, 33.9, 42.0, 51.1, 52.8, 62.3, 65.3,
125.8, 127.3, 127.9, 143.0, 172.1. Anal. (C16H21N) C, H, N.
Meth yl (1R,5S)-3â-p-tolyltr op a n e-2â-ca r boxyla te (2):
1H NMR (CDCl3) δ 1.54-1.78 (m, 3H), 2.00-2.24 (m, 2H), 2.22
(s, 3H), 2.29 (s, 3H), 2.58 (dt, 1H, J ) 2.7 and 12.3 Hz), 2.89
(t, 1H, J ) 3.6 Hz), 2.97 (dt, 1H, J ) 4.8 and 12.9 Hz), 3.32-
3.40 (m, 1H), 3.49 (s, 3H), 3.52-3.60 (m, 1H), 7.07 (d, 2H, J )
7.8 Hz), 7.14 (d, 2H, J ) 7.8 Hz); 13C NMR (CDCl3) δ 21.0,
25.2, 25.9, 33.3, 34.1, 42.0, 51.1, 52.8, 62.3, 65.3, 127.1, 128.6,
135.1, 139.9, 172.2. Anal. (C17H23N) C, H, N.
An examination of the data presented in Table 2
shows a significant difference in the 5HT/DA ratio
calculated from IC50 values from the binding experi-
ments in comparison to the selectivity ratio determined
using the calculated Ki values for binding. This differ-
ence arises because of the dependence of IC50 on ligand
concentration used, which for [3H]paroxetine was about
20 times its Kd of 40 pM, but the [3H]mazindol concen-
tration used was only 0.6 times its KD of 6 nM. Carroll
et al. used [3H]paroxetine at about 5 times its Kd and
[3H]WIN 35428 at about 0.04 times its Kd.6b,19 These
differences account for a significant portion of the
discrepancy in selectivity ratios reported for (()-33 and
probably for other compounds tested under nonidentical
conditions. The use of Ki values to calculate selectivity
ratios avoids problems associated with one of the most
common differences between laboratories in assays of
drug affinity for transporters. Note that upon using the
binding Ki’s, the selectivity ratios drop to 30 (from 289)
and 60 (from 586) for compounds 36 and 22, respec-
tively. Moreover, because both [3H]DA and [3H]5HT are
commonly used at about 0.1 times their Kd values in
uptake assays, the use of either IC50 or Ki values gives
similar selectivity ratios. For example, as can be seen
from Table 2, the selectivity ratios determined from
either the IC50 values or the Ki uptake values are
comparable and close to the selectivity ratios deter-
mined from the binding Ki’s. Similar observations can
be made using compounds 1 and 2, which exhibit less
transporter selectivity. Again, the selectivity ratios
determined from the binding and uptake Ki’s, or uptake
IC50’s, are comparable (1.5 versus 3.5 and 2.1 versus
3.4), while the selectivity ratios determined from bind-
ing IC50’s are 10-fold higher. Thus, while the use of Ki
values to determine selectivity ratios clearly does not
eliminate all the problems associated with comparing
pharmacological data between laboratories, it is helpful.
Meth yl (1R,5S)-3â-(p-flu or op h en yl)tr op a n e-2â-ca r box-
1
yla te (3): H NMR (CDCl3) δ 1.56-1.80 (m, 3H), 2.00-2.24
(m, 2H), 2.23 (s, 3H), 2.56 (dt, 1H, J ) 2.4 and 12.6 Hz), 2.86
(t, 1H, J ) 3.3 Hz), 2.97 (dt, 1H, J ) 5.1 and 12.6 Hz), 3.32-
3.40 (m, 1H), 3.50 (s, 3H), 3.52-3.60 (m, 1H), 6.95 (t, 2H, J )
8.4 Hz), 7.21 (dd, 2H, J ) 5.7 and 8.1 Hz); 13C NMR (CDCl3)
δ 25.1, 25.8, 33.2, 34.2, 41.9, 51.1, 52.8, 62.2, 65.2, 114.5 (d,
J C-F ) 20.7 Hz), 128.7 (d, J ) 7.7 Hz), 138.5, 161.0 (d, J C-F
241.2 Hz). Anal. (C16H20FN) C, H, N.
)
(1R,5S)-2â-F or m yl-3â-p h en yltr op a n e (4). To a solution
of 1 (0.50 g, 1.93 mmol) in THF (20 mL) was added portionwise
LiAlH4 (0.15 g, 3.85 mmol). The resulting mixture was stirred
at room temperature for 2 h, and a saturated solution of
Rochelle salt (30 mL) was added followed by extraction with
EtOAc (100 mL). The organic phase was washed with brine
(100 mL), dried, and concentrated under reduced pressure to
afford 0.35 g (79%) of the alcohol intermediate as a white
1
solid: mp 89-90 °C; H NMR (CDCl3) δ 1.43-1.50 (m, 1H),
1.57-1.66 (m, 1H), 1.73 (d, 1H, J ) 8.1 Hz), 1.67-1.80 (m,
1H), 2.04-2.24 (m, 2H), 2.27 (s, 3H), 2.51 (dt, 1H, J ) 2.7 and
12.9 Hz), 3.05 (dt, 1H, J ) 6.0 and 13.2 Hz), 3.28-3.35 (m,
1H), 3.39 (dd, 1H, J ) 2.1 and 10.8 Hz), 3.42-3.50 (m, 1H),
3.74 (dd, J ) 2.1 and 11.1 Hz), 7.10-7.40 (m, 5H); MS m/z
231 (M+, 12), 200 (14), 172 (12), 82 (100).
In summary, this work delineates the preparation of
a variety of 2-alkyl- and 2-aryl-substituted 3-aryltro-
panes through use of our oxidopyridinium betaine-based
dipolar cycloaddition strategy. Of particular interest is
the excellent binding affinity and selectivity for the DAT
over the 5HTT of the 2â-phenyl-3R-tolyltropane (22)
which adopts the boat conformation. This is the first
report of the preparation of such diaryltropanes in
optically pure form in both the chair and boat series.
In light of the excellent in vitro activity displayed by
some of these more unusual boat conformers, studies
of these compounds in drug discrimination paradigms
in animals will be reported in due course.
Oxalyl chloride (0.10 mL, 1.08 mmol) was dissolved in
anhydrous CH2Cl2 (10 mL), and the solution was cooled to -78
°C. DMSO (0.15 mL, 2.16 mmol) was added, and after 5 min
the above alcohol (0.25 g, 1.08 mmol) was added in CH2Cl2 (5
mL). Stirring was continued for 30 min. The reaction mixture
was quenched by adding Et3N (1.4 mL). The resulting solution
was warmed to room temperature, diluted with CH2Cl2 (30
mL), washed with NH4Cl (2 × 30 mL), dried, and concentrated
under reduced pressure to provide 0.21 g (84%) of 4 as a
colorless oil. This oil was used in the next step without further

4978 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Kozikowski et al.
purification: 1H NMR (CDCl3) δ 1.70 (d, 1H, J ) 8.4 Hz), 1.63-
1.78 (m, 1H), 1.91 (dt, 1H, J ) 3.6 and 12.9), 2.19 (s, 3H), 2.10-
2.28 (m, 2H), 2.40-2.56 (m, 2H), 3.18 (dt, 1H, J ) 5.4 and
13.2 Hz), 3.38-3.45 (m, 1H), 3.48-3.55 (m, 1H), 7.15-7.40 (m,
5H), 9.65 (d, 1H, J ) 3.0 Hz).
3.03 mmol), 0.63 g (80%) of 10 was obtained as a colorless oil:
1H NMR (CDCl3) δ 0.60-0.78 (m, 1H), 0.74 (t, 3H, J ) 7.2
Hz), 0.80-0.96 (m, 1H), 1.20-1.36 (m, 1H), 1.39-1.76 (m, 5H),
1.95-2.25 (m, 3H), 2.26 (s, 3H), 3.07 (dt, 1H, J ) 4.8 and 13.2
Hz), 3.14-3.22 (m, 1H), 3.22-3.30 (m, 1H), 6.98 (t, 2H, J )
8.7 Hz), 7.10 (dd, 2H, J ) 6.0 and 8.4 Hz); 13C NMR (CDCl3)
δ 14.1, 20.7, 24.7, 26.3, 29.1, 33.7, 35.6, 42.0, 46.0, 62.0, 64.7,
114.7 (d, J C-F ) 20.7 Hz), 128.9 (d, J C-F ) 7.7 Hz), 139.2 (d,
J C-F ) 3.2 Hz), 161.0 (d, J C-F ) 242.5 Hz). Anal. (C17H24FN‚
0.5H2O) C, H, N.
(1R,5S)-2â-F or m yl-3â-p-tolyltr op a n e (5). This compound
was prepared by the same procedure as that used to prepare
4. From 2 (0.80 g, 2.93 mmol) there was obtained 0.55 g (90%)
of 5 as a colorless oil: 1H NMR (CDCl3) δ 1.70 (d, 1H, J ) 8.7
Hz), 1.60-1.78 (m, 1H), 1.89 (dt, 1H, J ) 3.9 and 12.9), 2.19
(s, 3H), 2.30 (s, 3H), 2.10-2.33 (m, 2H), 2.39-2.53 (m, 2H),
3.14 (dt, 1H, J ) 5.7 and 12.9 Hz), 3.36-3.45 (m, 1H), 3.46-
3.55 (m, 1H), 7.10 (br s, 4H), 9.66 (d, 1H, J ) 3.3 Hz).
(1R,5S)-3â-(p-Flu or oph en yl)-2â-for m yltr opan e (6). This
compound was prepared similarly to 4. From 3 (0.90 g, 3.25
mmol) there was obtained 0.75 g (93%) of 6 as a colorless oil.
(1R,5S)-3â-P h en yl-2â-n -p r op yltr op a n e (7). A solution of
n-BuLi (2.20 mL, 2.62 mmol, 1.2 M in hexane) was dissolved
in THF (10 mL) and cooled to 0 °C. Ethyltriphenylphospho-
nium bromide (0.97 g, 2.62 mmol) was added slowly under
nitrogen. The resulting yellow-orange solution was stirred at
0 °C for 30 min, and then the cooling bath was removed. The
crude aldehyde 4 (0.20 g, 0.87 mmol) was added in THF (2
mL), and the reaction mixture was stirred for 15 h at room
temperature, diluted with EtOAc (20 mL), and washed with
NH4Cl (2 × 30 mL). The organic phase was extracted with
10% HCl (3 × 10 mL). The combined aqueous phases were
washed with EtOAc (30 mL), neutralized with a saturated
solution of NaHCO3, and extracted with CH2Cl2 (2 × 30 mL).
The combined organic phases were dried and concentrated
under reduced pressure, and the residue was purified by flash
chromatography (silica gel, ether/Et3N, 19:1) to afford 0.15 g
(71%) of the intermediate olefin as a mixture of the cis and
trans isomers.
Compounds 12a -c were prepared from 3-hydroxypyridine
by a procedure analogous to that described in ref 10.
1-Meth yl-4-p h en yl-3-p yr id in iu m ola te (12a ): mp 154-
1
157 °C; H NMR (DMSO-d6) δ 3.97 (s, 3 H), 7.30-7.52 (m, 5
H), 7.38 (d, 1 H, J ) 7.5 Hz), 8.04 (d, 1 H, J ) 8.1 Hz), 8.05 (s,
1 H).
1-Meth yl-4-p-tolyl-3-p yr id in iu m ola te (12b): mp 170-
172 °C; 1H NMR (CDCl3) δ 2.38 (s, 3H), 3.94 (s, 3 H), 6.95 (dd,
1H, J ) 2.1 and 6.0 Hz), 7.24 (d, 2H, J ) 8.1 Hz), 7.36 (d, 1H,
J ) 6.0 Hz), 7.43 (d, 1H, J ) 1.8 Hz), 7.89 (d, 2H, J ) 8.4 Hz).
4-(p-F lu or op h en yl)-11-m eth yl-3-p yr id in iu m ola te (12c):
1
mp 172-175 °C; H NMR (CDCl3) δ 3.97 (s, 3 H), 7.03-7.20
(m, 3 H), 7.34 (d, 1 H, J ) 6.3 Hz), 7.54 (s, 1 H), 7.90-8.00 (m,
2H).
(1S,5S,6R,Rs)-N-(Met h ylp h en yl)-6-(p -t olylsu lfin yl)-8-
azabicyclo[3.2.1]oct-3-en -2-on e (13). To a solution of 1-meth-
yl-4-phenyl-3-pyridiniumolate (12a ) (1.85 g, 10 mmol) in
dioxane (50 mL) was added (+)-(R)-p-tolyl vinyl sulfoxide (1.61
g, 10 mmol). The resulting solution was refluxed in dioxane
for 20 h and then concentrated under reduced pressure to give
a mixture of both exo and endo cycloadducts (70:30). Silica
gel flash column chromatography of the crude mixture led to
the separation of the 6-exo products (4:1 mixture of diastere-
omers, 55% overall yield) from the 6-endo product (one
diastereomer, 22% yield). The major 6-exo diastereomer 13
was obtained by crystallization from EtOAc of the 4:1 mix-
To a solution of the intermediate olefins (0.15 g) in MeOH
(10 mL) was added a catalytic amount of 5% Pt/C. The
mixture was shaken at room temperature for 30 min under a
hydrogen atmosphere at 40 psi in a Paar apparatus. The
solution was filtered over Celite and evaporated to dryness.
The resulting colorless oil was purified by flash chromatog-
raphy (silica gel, ether/Et3N, 19:1) to afford 0.13 g (95%) of 7
ture: [R]25 -51° (c 0.5, acetone); Rf 0.6 (EtOAc); mp 166 °C
D
1
(EtOAc); H NMR (CDCl3) δ 1.64 (dd, H7R, J ) 8.7 and 14.7
Hz), 2.14 (ddd, H7â, J ) 3.6, 7.5, and 14.7 Hz), 2.42 (s, 3H),
2.63 (s, 3H), 3.34 (dd, H6, J ) 3.3 and 8.7 Hz), 3.74 (d, H1, J )
7.5 Hz), 4.51 (d, H5, J ) 5.4 Hz), 7.02 (d, H4, J ) 5.1 Hz), 7.3-
7.4 (m, 7 H), 7.67 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ
21.5, 26.4, 34.7, 60.4, 69.3, 70.1, 125.4, 128.1, 128.3, 128.5,
130.2, 133.5, 138.6, 139.4, 141.3, 142.7, 197.0.
1
as a colorless oil: [R]D -97° (c 0.5, CH2Cl2); H NMR (CDCl3)
δ 0.71 (t, 3H, J ) 7.2 Hz), 0.78-0.95 (m, 1H), 1.20-1.35 (m,
1H), 1.38-1.56 (m, 2H), 1.56-1.75 (m, 3H), 1.97-2.26 (m, 3H),
2.25 (s, 3H), 3.07 (dt, 1H, J ) 5.1 and 13.2 Hz), 3.12-3.20 (m,
1H), 3.20-3.29 (m, 1H), 7.10-7.35 (m, 5H); 13C NMR (CDCl3)
δ 14.2, 20.8, 24.8, 26.4, 29.3, 33.6, 36.4, 42.1, 46.0, 62.0, 64.7,
125.6, 127.8, 128.0, 143.8; MS m/z 243 (M+, 11), 214 (8), 82
(100). Anal. (C17H25N) C, H, N.
(1S,5S,6R,Rs)-N-Met h yl-6-(p -t olylsu lfin yl)-3-p -t olyl-8-
a za bicyclo[3.2.1]oct-3-en -2-on e (14). This compound was
prepared similarly to 13. From a solution of 1-methyl-4-p-
tolyl-3-pyridiniumolate (12b) (1.86 g, 8.37 mmol) and (R)-(+)-
p-tolyl vinyl sulfoxide (1.07 g, 6.45 mmol) in dioxane (50 mL),
1.06 g (45%) of 14 was obtained as a white solid: [R]25 -47°
(1R,5S)-2â-n -P r op yl-3â-p-tolyltr op a n e (8). This com-
pound was prepared similarly to 7. From 5 (0.30 g, 1.24
D
1
(c 0.8, CH2Cl2); Rf 0.6 (EtOAc); mp 188 °C (EtOAc); H NMR
mmol), 0.19 g (60%) of 8 was obtained as a colorless oil: [R]25
(CDCl3) δ 1.65 (dd, H7R, J ) 8.7 and 14.7 Hz), 2.14 (ddd, H7â
,
D
1
-82° (c 0.5, CH2Cl2); H NMR (CDCl3) δ 0.72 (t, 3H, J ) 7.2
J ) 3.6, 7.8, and 14.7 Hz), 2.36 (s, 3H), 2.43 (s, 3H), 2.64 (s,
3H), 3.35 (dd, H6, J ) 3.3 and 8.7 Hz), 3.74 (d, H1, J ) 7.5
Hz), 4.51 (d, H5, J ) 5.1 Hz), 7.01 (d, H4, J ) 5.4 Hz), 7.17 (d,
2H, J ) 8.1 Hz), 7.27 (d, 2H, J ) 8.1 Hz), 7.35 (d, 2H, J ) 7.8
Hz), 0.80-0.96 (m, 1H), 1.20-1.36 (m, 1H), 1.39-1.56 (m, 2H),
1.56-1.75 (m, 3H), 1.96-2.26 (m, 3H), 2.25 (s, 3H), 2.31 (s,
3H), 3.04 (dt, 1H, J ) 4.8 and 13.2 Hz), 3.12-3.20 (m, 1H),
3.20-3.29 (m, 1H), 7.02 (d, 2H, J ) 8.1 Hz), 7.08 (d, 2H, J )
8.1 Hz); 13C NMR (CDCl3) δ 14.1, 20.7, 20.9, 24.8, 26.4, 29.1,
33.7, 35.9, 42.0, 45.9, 62.1, 64.7, 127.6, 128.7, 135.0, 140.5.
Anal. (C18H27N) C, H, N.
13
Hz), 7.68 (d, 2H, J ) 7.8 Hz); C NMR (CDCl3) δ 21.2, 21.4,
26.4, 34.7, 60.4, 69.3, 70.1, 125.4, 128.0, 128.9, 130.2, 130.5,
138.4, 139.4, 1340.6, 142.6, 197.2.
(1S,5S,6R,Rs)-3-(p-F lu or op h en yl)-N-m eth yl-6-(p-tolyl-
su lfin yl)-8-a za bicyclo[3.2.1]oct-3-en -2-on e (15). This com-
pound was prepared by the same procedure as used for 13.
From a solution of 1-methyl-4-(p-fluorophenyl)-3-pyridiniumo-
late (12c) (2.45 g, 12.04 mmol) and (R)-(+)-p-tolyl vinyl
sulfoxide (2.00 g, 12.04 mmol) in dioxane (25 mL), 1.78 g (40%)
of 15 was obtained as a white solid: [R]25D -77° (c 1.25, CHCl3);
Rf 0.2 (EtOAc/hexane, 7:3); mp 186 °C (EtOAc); 1H NMR
(1R,5S)-2â-n -Bu t yl-3â-p -t olylt r op a n e (9). This com-
pound was prepared similarly to 7. From 5 (0.30 g, 1.24
mmol), 0.20 g (60%) of 9 was obtained as a colorless oil: [R]D
1
-76° (c 1.5, CH2Cl2); H NMR (CDCl3) δ 0.74 (t, 3H, J ) 7.2
Hz), 0.70-0.90 (m, 2H), 1.12-1.30 (m, 3H), 1.39-1.68 (m, 5H),
1.96-2.20 (m, 3H), 2.24 (s, 3H), 2.31 (s, 3H), 3.03 (dt, 1H, J )
5.1 and 13.2 Hz), 3.12-3.20 (m, 1H), 3.20-3.28 (m, 1H), 7.03
(d, 2H, J ) 8.1 Hz), 7.08 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3)
δ 14.2, 21.0, 22.7, 24.8, 26.4, 26.7, 30.1, 33.8, 36.0, 42.1, 46.2,
62.1, 64.7, 127.7, 128.7, 135.0, 140.7; MS m/z 271 (M+, 6), 242
(2), 214 (4), 96 (40), 83 (100). Anal. (C19H29N‚1.1H2O) C, H,
N.
(CDCl
3) δ 1.64 (dd, H7R, J ) 8.7 and 14.7 Hz), 2.14 (ddd, H7â
,
J ) 3.6, 7.8, and 14.7 Hz), 2.42 (s, 3H), 2.62 (s, 3H), 3.33 (dd,
H6, J ) 3.6 and 8.7 Hz), 3.73 (d, H1, J ) 7.5 Hz), 4.51 (d, H5,
J ) 5.4 Hz), 7.01 (d, H4, J ) 5.4 Hz), 7.04 (t, 2H, J ) 8.7 Hz),
7.30-7.40 (m, 4H), 7.66 (d, 2H, J ) 8.1 Hz).
(1R,5S)-3â-(p-F lu or op h en yl)-2â-n -p r op yltr op a n e (10).
This compound was prepared similarly to 7. From 6 (0.75 g,
(1S,5R,7R,Rs)-N-Meth yl-4â-p h en yl-6â-(p-tolylsu lfin yl)-
3r-p-tolyl-8-a za bicyclo[3.2.1]octa n -2-on e (16). To a cooled

Synthesis, Biological Properties of New Tropanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 4979
(-78 °C) mixture of PhMgBr (0.55 mL, 1.65 mmol, 3.0 M in
ether), HMPA (0.57 mL, 3.28 mmol), and CuBr‚Me2S (14.0 mg,
0.07 mmol) was added dropwise a solution of 14 (500 mg, 1.37
mmol) and Me3SiCl (0.35 mL, 2.74 mmol) in dry THF (20 mL).
After 1 h, the reaction was quenched with a 20% solution of
NH4OH (20 mL), and the mixture was extracted with EtOAc
(30 mL). The organic phase was washed with brine (30 mL),
dried, and concentrated under reduced pressure. The crude
mixture containing the silyl enol ether intermediate was
diluted with MeOH (10 mL), and potassium fluoride was added
(160 mg, 2.74 mmol). The resulting solution was stirred at
room temperature for 5 min and then concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel using EtOAc/hexane as eluent
to afford 130 mg (22%) of the title compound as a pale-yellow
foam: Rf 0.65 (EtOAc/hexane, 1:1); 1H NMR (CDCl3) δ 2.04
(dd, 1H, J ) 8.7 and 11.7 Hz), 2.24 (s, 3H), 2.20-2.34 (m, 1H),
2.41 (s, 3H), 2.56 (s, 3H), 3.10 (t, 1H, J ) 8.4 Hz), 3.75 (d, 1H,
J ) 5.7 Hz), 3.85 (s, 1H), 4.09 (d, 1H, J ) 8.4 Hz), 6.66 (d, 2H,
J ) 8.1 Hz), 6.99 (d, 2H, J ) 7.8 Hz), 7.01-7.10 (m, 2H), 7.10-
7.20 (m, 3H), 7.30 (d, 2H, J ) 8.1 Hz), 7.55 (d, 2H, J ) 8.1
Hz); 13C NMR (CDCl3) δ 21.0, 21.4, 29.0, 39.7, 55.8, 58.2, 68.8,
72.3, 73.1, 76.6, 77.0, 77.2, 77.4, 124.1, 126.8, 127.0, 128.3,
129.0, 129.1, 130.1, 133.1, 136.5, 140.7, 142.0, 143.9, 211.7.
trated under reduced pressure, and the crude mixture was
purified by flash chromatography on silica gel using EtOAc/
hexane as eluent to afford 100 mg of the phenoxy(thiocarbo-
nyl)oxy derivative as a colorless oil: Rf 0.7 (EtOAc/hexane, 1:1);
1H NMR (CDCl3) δ 1.90 (dd, 1H, J ) 8.1 and 13.2 Hz), 1.95-
2.09 (m, 1H), 2.23 (s, 3H), 2.44 (s, 3H), 2.52 (s, 3H), 2.60 (d,
1H, J ) 11.1 Hz), 3.20 (t, 1H, J ) 7.5 Hz), 3.5 (br s, 1H), 3.64
(dd, 1H, J ) 5.1 and 11.1 Hz), 3.90-4.05 (m, 1H), 5.84 (dd,
1H, J ) 4.8 and 8.7 Hz), 6.76 (d, 2H, J ) 7.5 Hz), 6.82-7.42
(m, 14H), 7.56 (d, 2H, J ) 8.1 Hz).
A solution of the above intermediate (95 mg), Bu3SnH (133
µL, 0.49 mmol), and AIBN (16 mg, 0.01 mmol) in toluene (6
mL) was purged with argon. The reaction flask was placed
in a preheated oil bath at 60 °C and then heated to 90 °C for
1 h. After concentration under reduced pressure, the crude
residue was purified by flash chromatography on silica gel
using EtOAc/hexane as eluent to afford 53 mg (50%) of 19 as
a colorless oil: Rf 0.3 (EtOAc/hexane, 3:7); 1H NMR (CDCl3) δ
0.90 (t, 1H, J ) 12.3 Hz), 1.18-1.40 (m, 2H), 1.52 (dd, 1H, J
) 8.1 and 13.2 Hz), 2.08-2.20 (m, 1H), 2.22 (s, 3H), 2.40 (s,
3H), 2.51 (s, 3H), 3.00-3.18 (m, 1H), 3.31 (t, 1H, J ) 7.8 Hz),
3.40-3.55 (m, 1H), 3.62 (br s, 1H), 6.80 (d, 2H, J ) 8.1 Hz),
6.84-6.98 (m, 4H), 7.00-7.18 (m, 3H), 7.29 (d, 2H, J ) 8.1
Hz), 7.56 (d, 2H, J ) 8.1 Hz).
(1S,5R,7R,Rs)-3r-(p-F lu or op h en yl)-N-m eth yl-4â-p h en -
yl-6â-(p-tolylsu lfin yl)-8-a za bicyclo[3.2.1]octa n -2-on e (17).
This compound was prepared in the same manner as 16. From
14 (1.10 g, 2.98 mmol), 0.96 g (72%) of 17 was obtained as a
colorless oil: 1H NMR (CDCl3) δ 2.03 (dd, 1H, J ) 8.7 and
11.7 Hz), 2.25 (dd, 1H, J ) 6.9 and 8.1 Hz), 2.31 (d, 1H, J )
9.0 Hz), 2.40 (s, 3H), 2.57 (s, 3H), 3.09 (t, 1H, J ) 8.4 Hz),
3.74 (d, 1H, J ) 5.7 Hz), 3.85 (s, 1H), 4.14 (d, 1H, J ) 9.0 Hz),
6.73 (dd, 2H, J ) 5.4 and 8.4 Hz), 6.86 (t, 2H, J ) 8.7 Hz),
6.98-7.08 (m, 2H), 7.12-7.20 (m, 3H), 7.30 (d, 2H, J ) 8.1
Hz), 7.55 (d, J ) 8.1 Hz).
(1S,5R,7R,Rs)-3r-(p-F lu or op h en yl)-N-m eth yl-4â-n -p r o-
pyl-6â-(p-tolylsu lfin yl)-8-azabicyclo[3.2.1]octan -2-on e (18).
This compound was prepared in the same manner as 16. From
15 (1.50 g, 4.00 mmol), 1.34 g (80%) of 18 was obtained as a
pale-yellow oil: 1H NMR (CDCl3) δ 0.66 (t, 3H, J ) 7.2 Hz),
0.70-0.90 (m, 1H), 1.10-1.36 (m, 3H), 1.40-1.55 (m, 1H), 1.98
(dd, 1H, J ) 8.7 and 11.7 Hz), 2.20-2.35 (m, 1H), 2.42 (s, 3H),
2.53 (s, 3H), 2.92 (t, 1H, J ) 8.4 Hz), 3.54 (d, 1H, J ) 8.4 Hz),
3.61 (d, 1H, J ) 6.6 Hz), 3.64 (s, 1H), 6.89 (dd, 2H, J ) 5.4
and 8.4 Hz), 7.00 (t, 2H, J ) 8.7 Hz), 7.34 (d, 2H, J ) 8.1 Hz),
7.56 (d, J ) 8.1 Hz).
(1S,5R,7R,Rs)-2â-P h en yl-6â-(p-tolylsu lfin yl)-3r-p-tolyl-
tr op a n e (19). To a suspension of LiAH4 (22 mg, 0.59 mmol)
in dry THF (6 mL) was added a solution of 16 (130 mg, 0.29
mmol) in dry ether (20 mL). The resulting solution was stirred
at room temperature for 1 h and then quenched with a
saturated solution of NH4Cl. The resulting mixture was
extracted with ether (2 × 50 mL). The combined organic
phases were washed with brine (80 mL), dried, and concen-
trated under reduced pressure. The crude mixture was
purified by flash chromatography on silica gel using 60%
EtOAc/hexane as eluent to afford 120 mg (92%) of the alcohol
intermediate as a colorless oil: Rf 0.70 (EtOAc/hexane, 4:1);
1H NMR (CDCl3) δ 1.32 (br s, 1H), 1.72-1.88 (m, 1H), 2.20 (s,
3H), 2.41 (s, 3H), 2.51 (s, 3H), 2.40-2.60 (m, 1H), 2.70 (d, 1H,
J ) 11.4 Hz), 3.31 (8.1 Hz), 3.42 (dd, 1H, J ) 4.2 and 10.8
Hz), 3.56 (br s, 1H), 3.69 (t, 1H, J ) 6.6 Hz), 4.20-4.30 (m,
1H), 6.90-7.10 (m, 9H), 7.29 (d, 2H, J ) 8.1 Hz), 7.55 (d, 2H,
J ) 8.1 Hz).
To a solution of diisopropylamine (45 µL, 0.32 mmol) in dry
THF (4 mL) was added dropwise at 0 °C a solution of n-BuLi
(134 µL, 0.29 mmol, 2.2 M in hexane). The resulting solution
was stirred at 0 °C for 15 min and cooled to -78 °C, and a
solution of the alcohol intermediate (110 mg, 0.25 mmol) in
THF (5 mL) was added dropwise. After 5 min, phenyl
thionochloroformate (68 µL, 0.49 mmol) was added. After 1
h, the reaction was quenched with a saturated solution of NH4-
Cl (20 mL), and the mixture was extracted with ether (2 × 20
mL). The collected organic phases were dried and concen-
(1S,5R,7R,Rs)-3r-(p-Flu or oph en yl)-2â-ph en yl-6â-(p-tolyl-
su lfin yl)tr op a n e (20). This compound was prepared in the
same fashion as 19. From 17 (1.00 g, 2.23 mmol), 0.48 g (50%)
of 20 was obtained as a colorless oil: Rf 0.45 (EtOAc/hexane,
1:1); 1H NMR (CDCl3) δ 1.12-1.40 (m, 2H), 1.60 (dd, 1H, J )
8.7 and 12.9 Hz), 2.04-2.20 (m, 1H), 2.30 (d, 1H, J ) 10.2
Hz), 2.24-2.45 (m, 1H), 2.39 (s, 3H), 2.50 (s, 3H), 3.06 (ddd,
1H, J ) 6.9, 10.5, and 12.6 Hz), 3.28 (t, 1H, J ) 8.4 Hz), 3.42-
3.55 (m, 1H), 3.63 (br s, 1H), 6.73-6.94 (m, 6H), 7.02-7.16
(m, 3H), 7.27 (d, 2H, J ) 8.1 Hz), 7.55 (d, 2H, J ) 8.1 Hz).
(1S,5R,7R,Rs)-3r-(p -F lu or op h en yl)-2â-n -p r op yl-6â-(p -
tolylsu lfin yl)tr op a n e (21). This compound was prepared in
the same fashion as 19. From 18 (1.00 g, 2.42 mmol), 0.67 g
(70%) of 21 was obtained as a colorless oil: Rf 0.3 (EtOAc/
hexane, 1:1); 1H NMR (CDCl3) δ 0.62 (t, 3H, J ) 6.3 Hz), 0.68-
0.90 (m, 1H), 1.00-1.30 (m, 6H), 1.53 (dd, 1H, J ) 8.4 and
12.6 Hz), 2.00-2.15 (m, 1H), 2.20-2.60 (m, 2H), 2.38 (s, 3H),
2.44 (s, 3H), 3.17 (t, 1H, J ) 8.1 Hz), 3.28-3.42 (m, 1H), 3.39
(br s, 1H), 6.89 (t, 2H, J ) 8.7 Hz), 7.03 (dd, 2H, J ) 5.7 and
8.7 Hz), 7.30 (d, 2H, J ) 8.1 Hz), 7.56 (d, 2H, J ) 8.1 Hz); 13
C
NMR (CDCl3) δ 14.1, 19.4, 21.3, 32.0, 36.7, 39.4, 40.5, 41.3,
52.1, 60.5, 65.0, 72.5, 114.9 (d, J C-F ) 21.3 Hz), 124.3, 129.3
(d, J C-F ) 7.7 Hz), 129.9, 140.6 (d, J C-F ) 2.8 Hz), 141.2, 141.4,
161.2 (d, J C-F ) 242.5 Hz).
(1R,5S)-2â-P h en yl-3r-p-tolyltr op a n e (22). Phosphorus
trichloride (61 µL, 0.70 mmol) was added to a solution of 19
(50 mg, 0.12 mmol) in dry DMF (2.00 mL) at 0 °C. After being
stirred at 0 °C for 1 h, the reaction was quenched with a
saturated solution of NaHCO3 (20 mL) and extracted with
ether (2 × 20 mL). The combined organic phases were washed
with water (30 mL) and brine (30 mL), dried, and concentrated
under reduced pressure to afford 30 mg (61%) of the sulfide
intermediate as a colorless oil which was used in the next step
1
without further purification: Rf 0.5 (EtOAc/hexane, 1:9); H
NMR (CDCl3) δ 1.34 (dt, 1H, J ) 1.8 and 14.1 Hz), 2.10-2.35
(m, 2H), 2.23 (s, 3H), 2.42 (ddd, 1H, J ) 6.9, 10.2, and 13.8
Hz), 2.62 (s, 3H), 2.65 (d, 1H, J ) 10.5 Hz), 2.98-3.12 (m, 1H),
3.36 (br s, 1H), 3.50-3.60 (m, 1H), 3.70 (t, 1H, J ) 7.8 Hz),
6.85 (d, 2H, J ) 7.8 Hz), 6.94 (d, 2H, J ) 7.8 Hz), 7.02-7.26
(m, 9H); 13C NMR (CDCl3) δ 20.9, 39.0, 39.5, 42.1, 43.2, 52.7,
58.8, 60.5, 75.5, 125.9, 127.2, 127.9, 128.0, 128.7, 129.2, 129.6,
134.4, 135.4, 135.7, 140.9, 146.6.
Raney nickel was added to a solution of the sulfide (30 mg,
0.07 mmol) in ethanol (4 mL), and the resulting mixture was
refluxed for 1 h. Filtration through a pad of Celite and
concentration under reduced pressure afforded a crude mixture
that was purified by flash chromatography on silica gel using
ether/Et3N (19:1) as eluent to afford 15 mg (73%) of 22 as a
1
colorless oil: [R]25 -118° (c 0.3, CH2Cl2); H NMR (CDCl3) δ
D
1.32 (t, 1H, J ) 12.3 Hz), 1.50-1.75 (m, 2H), 2.10-2.38 (m,

4980 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Kozikowski et al.
2H), 2.23 (s, 3H), 2.31 (s, 3H), 2.44 (d, 1H, J ) 10.8 Hz), 2.42-
2.56 (m, 1H), 2.97 (dt, 1H, J ) 7.2 and 11.4 Hz), 3.27 (d, 1H,
J ) 6.6 Hz), 3.36 (t, J ) 6.6 Hz), 6.84 (d, 2H, J ) 7.8 Hz), 6.93
(d, 2H, J ) 7.8 Hz), 7.02-7.20 (m, 5H); 13C NMR (CDCl3) δ
20.9, 29.7, 29.8, 41.1, 41.3, 43.0, 58.6, 59.5, 68.1, 125.6, 127.3,
127.9, 128.1, 128.6, 135.1, 141.5, 147.6; MS m/z 291 (M+, 1),
178 (4), 115 (6), 96 (59), 82 (100). Anal. (C21H25N‚0.25H2O)
C, H, N.
CuCN (27 mg, 0.3 mmol) in dry ether (2 mL) at -7 °C was
added n-PrMgBr (3.0 mL, 1.0 M in ether). After 10 min, a
solution of 25 (570 mg, 1.5 mmol) in dry ether (5 mL) was
added dropwise. The resulting mixture was stirred at room
temperature for 1.5 h and then diluted with ether (20 mL).
The organic phase was washed with a saturated solution of
NH4Cl (2 × 20 mL), dried, and concentrated under reduced
pressure. The crude mixture was purified by flash chroma-
tography on silica gel using EtOAc/hexane as eluent to afford
(1R,5S)-3r-(p -F lu or op h en yl)-2â-p h en ylt r op a n e (23).
This compound was prepared in the same fashion as 22. From
420 mg (77%) of the title compound as a colorless oil: [R]25
D
+70° (c 1.5, acetone); Rf 0.7 (EtOAc/hexane, 3:7); 1H NMR
(CDCl3) δ 0.78 (t, 3H, J ) 7.2 Hz), 1.1-1.6 (m, 4H), 2.2-2.3
(m, 1H), 2.34 (s, 3H), 2.4-2.5 (m, 2H), 2.63 (s, 3H), 3.37 (br s,
1H), 3.51 (t, 1H, J ) 7.8 Hz), 3.60 (t, 1H, J ) 5.1 Hz), 6.10 (d,
20 (0.20 g, 0.46 mmol), 0.10 g (80%) of 23 was obtained as a
1
colorless oil: [R]25 -104° (c 0.4, CHCl3); H NMR (CDCl3) δ
D
1.26 (t, 1H, J ) 13.2 Hz), 1.50-1.69 (m, 2H), 2.15-2.39 (m,
2H), 2.31 (s, 3H), 2.38 (d, 1H, J ) 11.1 Hz), 2.42-2.53 (m,
1H), 2.98 (dt, 1H, J ) 6.9 and 11.4 Hz), 3.28 (d, 1H, J ) 6.0
Hz), 3.37 (t, J ) 6.6 Hz), 6.79 (t, 2H, J ) 8.4 Hz), 6.88 (t, 2H,
J ) 8.4 Hz), 7.02-7.14 (m, 5H); MS m/z 295 (M+, 1). Anal.
(C20H22FN) C, H, N.
1H, J ) 5.4 Hz), 7.13 (d, 2H, J ) 8.1 Hz), 7.2-7.3 (m, 7H); 13
C
NMR (CDCl3) δ 13.9, 21.0, 21.1, 34.3, 40.0, 42.1, 47.1, 49.7,
62.3, 70.5, 126.0, 127.1, 128.3, 129.6, 129.7, 130.0, 134.0, 136.2,
138.4, 140.2.
(1S,5S,7R)-N-Met h yl-2,3-d ip h en yl-6â-(p -t olylt h io)-8-
a za bicyclo[3.2.1]oct-3-en e (28). This compound was pre-
pared in the same fashion as 27. From the allylic acetate 25
(0.50 g, 1.45 mmol) there was obtained 70 mg (12%) of 28 as
a colorless oil: 1H NMR (CDCl3) δ 2.3-2.4 (m, 1H), 2.37 (s,
3H), 2.43 (s, 3H), 2.52 (dd, 1H, J ) 8.1 and 12.3 Hz), 3.40 (s,
1H), 3.67 (t, 1H, J ) 7.5 Hz), 3.75 (br s, 1H), 6.51 (d, 1H, J )
5.7 Hz), 7.0-7.5 (m, 14H).
(1S,5S,7R)-N-Met h yl-2â-n -p r op yl-3-p-t olyl-6â-(p-t olyl-
th io)-8-a za bicyclo[3.2.1]oct-3-en e (29). This compound was
prepared in the same fashion as 27. From the allylic acetate
26 (165 mg, 0.42 mmol), 145 mg (91%) of 29 was obtained as
a colorless oil: [R]D +110° (c 2.6, CH2Cl2); Rf 0.5 (EtOAc/
hexane, 1:4); 1H NMR (CDCl3) δ 0.81 (t, 3H, J ) 7.2 Hz), 1.2-
1.6 (m, 4H), 2.2-2.3 (m, 1H), 2.35 (s, 3H), 2.4-2.5 (m, 2H),
2.65 (s, 3H), 3.39 (br s, 1H), 3.53 (t, 1H, J ) 7.8 Hz), 3.60 (t,
1H, J ) 5.4 Hz), 6.08 (d, 1H, J ) 6.0 Hz), 7.10-7.24 (m, 6H),
7.32 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 14.0, 21.0, 21.1,
34.3, 40.0, 42.1, 47.1, 49.7, 62.3, 70.6, 125.8, 128.8, 129.0, 129.7,
129.9, 134.1, 136.1, 136.9, 137.3, 138.2.
(1S,5S,7R)-2â-n -Bu tyl-N-m eth yl-3-p-tolyl-6â-(p-tolylth io)-
8-a za bicyclo[3.2.1]oct-3-en e (30). This compound was pre-
pared in the same fashion as 27. From the allylic acetate 26
(200 mg, 0.51 mmol) there was obtained 140 mg (70%) of 30
as a colorless oil: [R]D +79° (c 1.0, EtOH); 1H NMR (CDCl3) δ
0.80 (t, 3H, J ) 6.6 Hz), 1.00-1.40 (m, 5H), 1.40-1.60 (m, 1H),
2.20-2.50 (m, 3H), 2.32 (s, 3H), 2.33 (s, 3H), 2.63 (s, 3H), 3.35
(s, 1H), 3.50 (t, 1H, J ) 7.2 Hz), 3.58 (t, 1H, J ) 5.1 Hz), 6.06
(d, 1H, J ) 5.4 Hz), 7.00-7.20 (m, 6H), 7.31 (d, 2H, J ) 8.1
Hz); 13C NMR (CDCl3) δ 14.0, 20.9, 21.0, 22.5, 30.3, 31.7, 39.9,
42.1, 47.3, 49.8, 62.3, 70.4, 125.8, 128.7, 129.0, 129.7, 130.2,
134.0, 136.2, 136.8, 137.2, 138.2.
(1S,5S,7R)-N-Meth yl-2â-ph en yl-3-p-tolyl-6â-(p-tolylth io)-
8-a za bicyclo[3.2.1]oct-3-en e (31). This compound was pre-
pared in the same fashion as 27. From the allylic acetate 26
(0.34 g, 0.85 mmol), 0.10 g (27%) of 31 was obtained as a
colorless oil: 1H NMR (CDCl3) δ 2.20-2.35 (m, 1H), 2.22 (s,
3H), 2.37 (s, 3H), 2.42 (s, 3H), 2,50 (dd, 1H, J ) 8.4 and 12.6
Hz), 3.39 (s, 1H), 3.67 (t, 1H, J ) 8.4 Hz), 3.66-3.78 (m, 2H),
6.48 (d, 1H, J ) 5.4 Hz), 6.96 (d, 2H, J ) 8.1 Hz), 7.00-7.30
(m, 9H), 7.36 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 21.0,
21.1, 40.1, 41.7, 49.8, 52.9, 62.2, 75.6, 115.3, 120.2, 125.4, 125.8,
127.9, 128.1, 128.9, 129.8, 130.2, 130.5, 133.9, 134.0, 136.4,
136.7, 142.7.
(1R,5S)-3r-(p-F lu or op h en yl)-2â-n -p r op yltr op a n e (24).
This compound was prepared in the same fashion as 22. From
21 (0.20 g, 0.50 mmol), 91 mg (70%) of 24 was obtained as a
1
colorless oil: [R]25 -40° (c 0.25, CHCl3); H NMR (CDCl3) δ
D
0.77 (t, 3H, J ) 6.9 Hz), 1.08-1.47 (m, 8H), 2.10-2.20 (m, 2H),
2.28 (s, 3H), 2.31-2.58 (m, 2H), 2.94 (d, 1H, J ) 5.1 Hz), 3.20
(t, 1H, J ) 8.1 Hz), 6.93 (t, 2H, J ) 8.4 Hz), 7.10 (t, 2H, J )
8.4 Hz); MS m/z 261 (M+, 1). Anal. (C17H24FN) C, H, N.
(1S,5S,6R)-2-Acetoxy-N-m eth yl-3-ph en yl-6â-(p-tolylth io)-
8-a za bicyclo[3.2.1]oct-3-en e (25). Enone 13 (600 mg, 1.71
mmol) was dissolved in a solution of CeCl3‚7H2O (700 mg, 1.88
mmol) in MeOH (10 mL); then NaBH4 (71 mg, 1.88 mmol) was
added portionwise. This mixture was stirred at room tem-
perature for 15 min, then concentrated under reduced pres-
sure, diluted with water (30 mL), and extracted with EtOAc
(3 × 30 mL). The combined organic phases were washed with
brine (50 mL), dried, and concentrated under reduced pressure
to afford the allylic alcohol intermediate (620 mg).
To a solution of the crude alcohols (620 mg) in pyridine (6
mL) was added Ac2O (2 mL). The resulting solution was
stirred at room temperature for 15 h, then concentrated under
reduced pressure, diluted with EtOAc (50 mL), and washed
with NH4Cl (2 × 40 mL). Drying and concentration under
reduced pressure afforded a crude mixture of the allylic
acetates (660 mg, 97%) that was used in the next step without
purification.
Phosphorus trichloride (0.85 mL, 9.7 mmol) was added to a
solution of the sulfoxide intermediate (660 mg) in dry DMF
(15 mL) at 0 °C. After being stirred at 0 °C for 1 h, the reaction
was quenched with a saturated solution of NaHCO3 (60 mL)
and extracted with ether (2 × 50 mL). The combined organic
phases were washed with water (50 mL) and brine (50 mL),
dried, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel
using EtOAc/hexane as eluent to afford 570 mg (88%) of the
title compound as a 3:1 mixture of two isomers; Rf 0.7 (EtOAc/
hexane, 3:7). Major isomer: 1H NMR (CDCl3) δ 1.91 (s, 3H),
2.34 (s, 3H), 2.72 (s, 3H), 6.23 (d, 1H, J ) 5.1 Hz), 6.33 (d, 1H,
J ) 4.8 Hz). Minor isomer: 1H NMR (CDCl3) δ 1.94 (s, 3H),
2.32 (s, 3H), 2.61 (s, 3H), 5.39 (s, 1H), 6.37 (d, 1H, J ) 5.7
Hz).
(1S,5S,6R)-2-Acetoxy-N-m eth yl-3-p-tolyl-6â-(p-tolylth io)-
8-a za bicyclo[3.2.1]oct-3-en e (26). This compound was pre-
pared in the same manner as 25. From enone 14 (0.60 g, 1.64
mmol) there was obtained 585 mg (90%) of 26 as a 3:1 mixture
of two isomers: Rf 0.7 (EtOAc/hexane, 3:7). Major isomer (R-
acetoxy derivative): 1H NMR (CDCl3) δ 1.92 (s, 3H), 2.34 (s,
3H), 1.90-2.06 (m, 1H), 2.33 (s, 3H), 2.34 (s, 3H), 2.72 (s, 3H),
2.65-2.80 (m, 1H), 3.43 (d, 1H, J ) 5.1 Hz), 3.65-3.84 (m,
2H), 6.20 (d, 1H, J ) 5.1 Hz), 6.32 (d, 1H, J ) 4.5 Hz), 7.05-
7.20 (m, 6H), 7.31 (d, 2H, J ) 7.8 Hz). Minor isomer (â-acetoxy
derivative): 1H NMR (CDCl3) δ 1.96 (s, 3H), 2.10-2.25 (m,
1H), 2.33 (s, 3H), 2.34 (s, 3H), 2.60 (s, 3H), 3.50-65 (m, 3H),
5.38 (s, 1H), 6.33 (d, 1H, J ) 5.4 Hz), 7.05-7.30 (m, 8H).
(1S,5S,7R)-N-Meth yl-3-p h en yl-2â-n -p r op yl-6â-(p-tolyl-
th io)-8-a za bicyclo[3.2.1]oct-3-en e (27). To a suspension of
(1R,5S)-3-P h en yl-2â-n -p r op yltr op a n e (7 a n d 35). Raney
Ni was added to a solution of 27 (70 mg, 0.19 mmol) in ethanol
(4 mL), and the resulting mixture was refluxed for 2 h.
Filtration through a pad of Celite and concentration under
reduced pressure afforded a mixture containing the two
isomers 7 and 35 (ratio 3:1 by GC-MS analysis). These
isomers were separated by preparative thin-layer chromatog-
raphy on silica gel using EtOAc/hexane/Et3N (8:90:2) as eluent
to afford the title compounds as colorless oils. 3â-Isomer 7
(6.0 mg, 13%): [R]25 -95° (c 0.25, CH2Cl2). 3R-Isomer 35 (10
D
mg, 43%): [R]25D -50° (c 1.0, CH2Cl2); 1H NMR (CDCl3) δ 0.77
(t, 3H, J ) 7.5 Hz), 1.0-1.6 (m, 8H), 2.0-2.3 (m, 2H), 2.23 (s,

Synthesis, Biological Properties of New Tropanes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 4981
3H), 2.32-2.60 (m, 2H), 2.95 (d, 1H, J ) 6.0 Hz), 3.21 (br t,
1H, J ) 7.5 Hz), 7.1-7.35 (m, 5H); 13C NMR (CDCl3) δ 14.2,
19.0, 29.0, 29.5, 37.0, 40.6, 41.6, 41.8, 50.6, 59.5, 65.0, 125.7,
128.1, 128.2, 146.2; MS m/z 243 (M+, 5), 214 (3), 96 (42), 83
(100). Anal. (C17H25N‚0.1H2O) C, H, N.
and radioligand, and binding was stopped by filtration after a
1-h incubation at 4 °C with [3H]mazindol and at room tem-
perature with [3H]paroxetine. Nonspecific uptake or binding
was defined in all assays by 100 µM cocaine. This concentra-
tion of cocaine gave estimates of nonspecific binding and
uptake identical to more selective transport inhibitors such
as 10 µM fluoxetine and 10 µM nomifensine. Other details of
the assays are as referenced above.
(1R,5S)-2â,3-Dip h en yltr op a n e (33 a n d 36). This com-
pound was prepared in the same fashion as 7 and 35. From
28 (0.13 g, 0.33 mmol), 0.03 g (33%) of the 3â-isomer 33 and
0.02 g (22%) of the 3R-isomer 36 were obtained as colorless
oils. Compound 33: [R]25 -76° (c 1.0, CH2Cl2); 1H NMR
D
Ack n ow led gm en t. We are indebted to the National
Institutes of Health, National Institute on Drug Abuse
(DA10458) for their support of these studies.
(CDCl3) δ 1.64 (dt, 1H, J ) 4.2 and 13.5 Hz), 1.72-1.86 (m,
2H), 2.06-2.30 (m, 2H), 2.25 (s, 3H), 2.39 (dt, 1H, J ) 2.4 and
12.9 Hz), 2.84-2.92 (m, 1H), 3.26-3.42 (m, 3H), 6.85 (d, 2H,
J ) 8.1 Hz), 6.95-7.12 (m, 5H), 7.35-7.45 (m, 2H); 13C NMR
(CDCl3) δ 25.1, 27.3, 35.2, 37.5, 42.0, 53.3, 61.9, 67.7, 125.4,
125.5, 127.0, 127.5, 128.0, 130.6, 142.8, 143.2. Anal. (C20H23N‚
Refer en ces
(1) J ohanson, C.-E.; Fischman, M. W. The Pharmacology of Cocaine
Related to its Abuse. Pharmacol. Rev. 1989, 41, 3-52. Clouet,
D., Asghar, K., Brown, R., Eds. Mechanisms of Cocaine Abuse
and Toxicity. NIDA Res. Monogr. 1988, 88.
0.25H2O) C, H, N. Compound 36: [R]25 -55° (c 0.2, CH2Cl2);
D
1H NMR (CDCl3) δ 1.38 (t, 1H, J ) 13.2, 1.54-1.80 (m, 2H),
2.16-2.40 (m, 2H), 2.35 (s, 3H), 2.44-2.60 (m, 2H), 2.96-3.10
(m, 1H), 3.32 (d, 1H, J ) 6.3 Hz), 3.36-3.46 (m, 1H), 6.98 (d,
2H, J ) 8.1 Hz), 7.00-7.20 (m, 8H); 13C NMR (CDCl3) δ 29.7,
29.8, 40.9, 41.3, 43.6, 58.7, 59.5, 68.1, 125.7, 125.8, 127.3, 127.9,
128.0, 128.3, 144.6, 147.5. Anal. (C20H23N‚0.5H2O) C, H, N.
(2) Kleber, H. D.; Gawin, F. H. Cocaine: Pharmacology, Effects, and
Treatment of Abuse. NIDA Res. Monogr. 1984, 50, 111-129.
Pulvirenti, L.; Koob, G. F. Dopamine receptor agonists, partial
agonists and psychostimulant addiction. Trends Pharmacol. Sci.
1994, 15, 374-379. J ohnson, K. M.; Bergmann, J . S.; Kozikows-
ki, A. P. Cocaine and dopamine differentially protect [3H]-
mazindol binding sites from alkylation by N-ethylmaleimide.
Eur. J . Pharmacol., Mol. Pharmacol. Sect. 1992, 227, 411-415.
(3) Unpublished data, manuscript in preparation. Also, see: Mate-
cka, D.; Lewis, D.; Rothman, R. B.; Dersch, C. M.; Wojnicki, F.
H.; Glowa, J . R.; De Vries, A. C.; Pert, A.; Rice, K. C. Heteroaro-
matic analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis-
(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines
(GBR 12935 and GBR 12909) as high-affinity dopamine reuptake
inhibitors. J . Med. Chem. 1997, 40, 705-716 and references
therein.
(4) Carroll, F. I.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Cocaine
receptor: Biochemical characterization and structure-activity
relationships for the dopamine receptor. J . Med. Chem. 1992,
35, 969-981. Kozikowski, A. P.; Araldi, G. L.; Boja, J .; Meil, W.
M.; J ohnson, K. M.; Flippen-Anderson, J . L.; George, C.; Saiah,
E. Chemistry and pharmacology of the piperidine-based ana-
logues of cocaine. Identification of potent DAT inhibitors lacking
the tropane skeleton. J . Med. Chem. 1998, 41, 1962-1969 and
references therein.
(1S,5S,7R)-N-Meth yl-2â-p h en yl-3â-p-tolyltr op a n e (34).
This compound was prepared in the same fashion as 7. From
31 (0.09 g, 0.21 mmol) there was obtained 0.03 g (50%) of 34
as a colorless oil: [R]25D -160° (c 0.2, CH2Cl2); 1H NMR (CDCl3)
δ 1.62 (dt, 1H, J ) 4.2 and 13.5 Hz), 1.72-1.86 (m, 2H), 2.04-
2.30 (m, 2H), 2.17 (s, 3H), 2.23 (s, 3H), 2.36 (dt, 1H, J ) 2.4
and 12.9 Hz), 2.84-2.92 (m, 1H), 3.24-3.42 (m, 3H), 6.74 (d,
2H, J ) 8.1 Hz), 6.85 (d, 2H, J ) 8.1 Hz), 7.00-7.15 (m, 3H),
7.37-7.45 (m, 2H); 13C NMR (CDCl3) δ 20.9, 25.1, 27.3, 35.5,
37.0, 42.0, 53.2, 62.0, 67.8, 125.4, 127.0, 127.8, 128.2, 130.7,
134.8, 140.1, 143.0; MS m/z 291 (M+, 8), 178 (4), 96 (60), 82
(100). Anal. (C21H25N) C, H, N.
(1S,5S,7R)-N-Meth yl-2â-n -pr opyl-3r-p-tolyltr opan e (37).
This compound was prepared in the same fashion as 7. From
29 (0.12 g, 0.32 mmol) there was obtained 45 mg (55%) of 37
as a colorless oil: 1H NMR (CDCl3) δ 0.78 (t, 3H, J ) 7.2 Hz),
1.08-1.56 (m, 8H), 2.04-2.24 (m, 2H), 2.23 (s, 3H), 2.30 (s,
3H), 2.28-2.58 (m, 2H), 2.94 (d, 1H, J ) 6.3 Hz), 3.19 (t, 1H,
J ) 7.8 Hz), 7.06 (s, 4H); 13C NMR (CDCl3) δ 14.2, 19.9, 21.0,
29.0, 29.5, 37.0, 40.1, 41.6, 41.9, 50.6, 59.6, 64.9, 128.1, 128.8,
135.1, 143.1. Anal. (C18H27N) C, H, N.
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(1S,5S,7R)-2â-n -Bu tyl-N-m eth yl-3-p-tolyltr op a n e (38).
This compound was prepared in the same fashion as 7. From
30 (0.20 g, 0.51 mmol) there was obtained 45 mg (55%) of 37
as a colorless oil: [R]25D -42° (c 0.5, CH2Cl2); 1H NMR (CDCl3)
δ 0.80 (t, 3H, J ) 6.6 Hz), 1.08-1.56 (m, 10H), 2.04-2.24 (m,
2H), 2.23 (s, 3H), 2.30 (s, 3H), 2.28-2.58 (m, 2H), 2.94 (d, 1H,
J ) 6.0 Hz), 3.19 (t, 1H, J ) 7.8 Hz), 7.06 (s, 4H); 13C NMR
(CDCl3) δ 14.1, 20.9, 22.8, 28.9, 29.0, 29.5, 34.3, 40.0, 41.6,
41.8, 50.8, 59.5, 64.9, 128.1, 128.8, 135.1, 143.1. Anal.
(C19H29N‚1.15H2O) C, H, N.
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Up ta k e a n d Bin d in g Meth od s. The uptake of [3H]-
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mazindol.3,15 In these studies the approximate concentrations
of radioligands used (along with the Kd value used in the
Cheng-Prusoff caculation of Ki) are as follows: [3H]DA, 5 nM
(57 nM); [3H]5HT, 5 nM (52 nM); [3H]mazindol, 4 nM (6 nM);
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identical buffer for all assays.16 This Krebs-Ringer-HEPES
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MgSO4, and 25 mM HEPES (pH 7.4). Cocaine and other
compounds were added to the incubation mixture 30 min prior
to the initiation of [3H]DA or [3H]5HT uptake to ensure
equilibration. Uptake was stopped by rapid filtration after 5
min as previosuly described.14 Binding assays were initiated
by adding striatal tissue homogenate to tubes containing drugs
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