An enantioselective synthesis and biobehavioral evaluation of 7-fluoro-3-(p-fluorophenyl)-2-propyltropanes

Article abstract of DOI:10.1016/S0960-894X(00)00269-9

Optically pure 7-fluorotropanes 3a-c, were synthesized as structural probes of the dopamine transporter. The synthesis of these compounds was accomplished through the asymmetric 1,3-dipolar cycloaddition reaction of the oxidopyridinium betaine 4 with the chiral dipolarophile (R)-p-tolyl vinyl sulfoxide. In the preliminary analysis, tropane 3a was found to reduce the rewarding effects of cocaine in the brain stimulation reward paradigm. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00269-9

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1443±1446
An Enantioselective Synthesis and Biobehavioral Evaluation
of 7-Fluoro-3-(p-¯uorophenyl)-2-propyltropanes
K. R. C. Prakash,a Monika Trzcinska,b Kenneth M. Johnsonc
and Alan P. Kozikowskia,*
aGeorgetown University Medical Center, Drug Discovery Program, Institute for Cognitive and Computational Sciences,
3970 Reservoir Road NW, Washington, DC 20007-2197, USA
bDepartment of Psychology, Northeastern University, 125 Nightingale Hall, Boston, MA 02115, USA
cDepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
Received 3 March 2000; accepted 24 April 2000
AbstractÐOptically pure 7-¯uorotropanes 3a±c, were synthesized as structural probes of the dopamine transporter. The
synthesis of these compounds was accomplished through the asymmetric 1,3-dipolar cycloaddition reaction of the oxidopyr-
idinium betaine 4 with the chiral dipolarophile (R)-p-tolyl vinyl sulfoxide. In the preliminary analysis, tropane 3a was found
to reduce the rewarding e€ects of cocaine in the brain stimulation reward paradigm. # 2000 Elsevier Science Ltd. All rights
reserved.
Cocaine abuse is a major health and social problem
worldwide, and thus strategies are needed to solve this
addiction problem.1 The predominant theoretical expla-
nation for cocaine's behavioral e€ects is the so-called
`dopamine hypothesis'.2 According to this hypothesis,
the reinforcing properties of cocaine are the direct result
of inhibition of dopamine (DA) reuptake. Since the
dopamine transporter (DAT) is the primary mechanism
for the removal of DA from the synaptic cleft after its
release,3 inhibition of DA reuptake results in a buildup of
DA, leading to signi®cant potentiation of dopaminergic
transmission. In addition to the DAT, cocaine also
binds with high anity to the serotonin (SERT) and the
norepinephrine transporters (NET).4 Recent ®ndings
suggest that both the SERT and the NET may also play
prominent roles in cocaine addiction.5 As such, we believe
it to be of continued value to explore the e€ects of novel
ligands that show varying levels of transporter selectivity
in behavioral models, with the aim to better de®ne the
transporter pro®le(s) and ligand structures that may
lead to useful medications.6
loss in binding anity compared to the 6- and 7-unsub-
stituted compounds. However, of some biological interest
with respect to this 2-carbon bridge substituted series was
our earlier ®nding that the methoxylated pseudococaine 2,
although showing poor binding anity, was able to
antagonize cocaine's ability to inhibit dopamine reuptake
in a functional assay.7a Based upon this ®nding, together
with preliminary work that revealed the ability of certain
racemic, ¯uorinated tropane analogues to maintain good
transporter activity, we now chose to investigate the
chemistry and biology of the optically pure analogues 3a±c
(Fig. 1).
Chemistry
A variety of methods have now been detailed in the lit-
erature for the preparation of 6- and 7-substituted tropane
analogues.7 The synthetic strategies employed include a
double Mannich reaction,7a a [3+2] cycloaddition
reaction,7c,7e g and the intramolecular cyclization of
substituted aminocycloheptane derivatives.7d
Previously, we have studied the synthesis and transporter
activity of 3-aryltropanes with a substituent on the 2-car-
bon bridge, (i.e., the 6- and 7-substituted tropanes,7) and
we have shown that such substitution generally leads to a
The compounds required for the present study were
conveniently prepared by use of our previously disclosed
oxidopyridinium ion-based dipolar cycloaddition strategy.
As detailed in the accompanying Scheme 1, the 1,3-
dipolar cycloaddition8 of betaine 4,9 with (R)-p-tolyl
vinyl sulfoxide was investigated.
*Corresponding author. Tel.: +1-202-687-0686; fax: +1-202-687-
5065; e-mail: kozikowa@giccs.georgetown.edu
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00269-9

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K. R. C. Prakash et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1443±1446
Figure 1.
Scheme 1. Reagents and conditions: (a) (R)-p-tolyl vinyl sulfoxide, dioxane, re¯ux, 24 h.
The required cycloaddition reaction was performed in
dioxane at re¯ux for 24 h to give, with complete regio-
selectivity, a mixture of exo and endo cycloadducts in a
70:30 ratio. Silica gel ¯ash column chromatography of the
crude mixture led to the separation of the exo tropenones
5a and 5b (4:1 mixture of the diastereomers) from the
endo tropenone 5c. The major exo diastereomer 5a was
obtained in 45% yield by crystallization of the above mix-
ture from EtOAc and had [a]2d5 77ꢀ (c 1.25, CHCl3) and
mp 186 ꢀC. The absolute con®guration of 5a was deter-
mined by comparing its NMR and optical rotation data
with those of similar compounds previously reported.8
outcome can be explained by the neighboring group
participation of the ring nitrogen.
To prepare the b-¯uoro compound 3b, we used a two-step
protocol which involved ¯uorination of the sulfone 8 fol-
lowed by reductive desulfonylation. The ¯uorination was
achieved by treating the sulfone with n-BuLi/N-¯uoro-
benzenesulfonimide to a€ord the ¯uorosulfone 11 in
70% yield.14 The structure was con®rmed by comparing
the NMR data with those of a similar compound
reported earlier.7b The reductive desulfonylation15 of 11
readily a€orded the tropanes 3a and 3b in a 4:1 ratio.
Treatment of the ketone 9 with DAST13 gave the 7,7-
di¯uorotropane 3c in 50% yield.16
Copper catalyzed 1,4-addition of n-PrMgBr to trope-
none 5a in the presence of TMSCl and HMPA followed
by reduction of the ketone thus obtained with LiBH4
a€orded the alcohol 6 exclusively (Scheme 2). Barton
type deoxygenation10 then gave the tropane 7 in 50%
yield. Oxidation of the sulfoxide with MoOPH was not
satisfactory (low yield), and to overcome this problem
the sulfoxide 7 was oxidized to sulfone 8 using oxone as
oxidizing agent.11 The yields were not satisfactory with
other oxidizing agents (m-CPBA, t-BuOOH, H2O2, etc.),
whereas oxone gave an 87% yield. Compound 8 was
further oxidized with MoOPH12 to a€ord the ketone 9,
which was reduced in turn to alcohol 10 with DIBAL-
H. The alcohol 10 was converted by treatment with
DAST13 exclusively to the a-¯uoride 3a as shown by
comparison of its 1H NMR spectrum with that of a
known reference compound.7b While an SN2 displacement
should have given the b-¯uoro compound, the observed
Pharmacological and Behavioral Studies
The tropanes reported in this series were tested 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.17 This
ligand binds with high anity (Kd=8.63 Æ 0.53 nM) to
a single, sodium-dependent site on the dopamine carrier
in striatal membranes. Additionally, these compounds
were tested for their ability to inhibit high-anity uptake
of [3H]DA, [3H]NE, and [3H]5-HT into striatal, parietal
and occipital cortex, and midbrain nerve endings
(synaptosomes), respectively.18 The binding and uptake
data are provided in Table 1 along with comparison
data for cocaine.

K. R. C. Prakash et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1443±1446
1445
Scheme 2. Reagents and conditions: (a) n-PrMgBr, CuBrꢁ Me2S, TMSCl, HMPA, THF, 78 ꢀC; (b) LiBH4, THF, rt; (c) n-BuLi, THF, then
PhOC(S)Cl, 78 ꢀC; (d) n-Bu3SnH, AIBN, toluene, 60 ꢀC; (e) oxone, MeOH/H2O (2:1), rt; (f) n-BuLi, MoOPH, THF, 78 ꢀC; (g) DIBAL-H,
CH2Cl2, 0 ꢀC; (h) DAST, CH2Cl2, rt; (i) n-BuLi, N-¯uorobenzenesulfonimide, THF, 78 ꢀC to rt; (j) 6% Na(Hg), Na2HPO4, MeOH, rt.
Table 1. Ki values (nM) for the tropane analogues in mazindol binding and dopamine, serotonin and norepinephrine reuptake experiments
Compound
R
R0
[3H]mazindol binding
[3H]DA uptake
[3H]5-HT uptake
[3H]NE uptake
Cocaine
280 Æ 16
30 Æ 1
420 Æ 150
49 Æ 7
160 Æ 1
561 Æ 32
1250 Æ 40
7910 Æ 70
108 Æ 4
52 Æ 1
3a
3b
3c
H
F
F
F
H
F
1150 Æ 50
860 Æ 60
304 Æ 1
126 Æ 13
3790 Æ 100
1450 Æ 50
Pharmacological experiments revealed 3a to be the most
DAT-potent of the three ¯uorinated analogues presented
here, inhibiting mazindol binding with a Ki of 30.0 nM
and dopamine reuptake with a Ki of 49.0 nM, as com-
pared to 280 and 420 nM for ( )-cocaine. Analogues 3b
and 3c were less active, showing anities of 1150 and
860 nM in mazindol binding and Kis of 304 and 1450
nM in the dopamine reuptake studies, respectively. The
parent compound lacking substitution on the 2-carbon
bridge showed an anity of 21.1 nM in the mazindol
binding studies and a Ki of 12.1 nM in the DA reuptake
studies.19 As is also apparent from Table 1, 3a±3c show
poor SERT activity, while the NET potency of 3a is
comparable to its DAT potency.
trained to bar press for electrical stimulation of that
structure, as described previously.20,21 The data, obtained
under the baseline and drug conditions, were compared
and two variables were analyzed: (1) The maximum
response rate, which re¯ects the motor/performance
capacity. (2) The frequency of stimulation necessary to
sustain half-maximal rate of responding, a measure
re¯ecting reward threshold. Cocaine (as little as 10 mg/kg)
is well known to enhance reward, by lowering the reward
threshold necessary to maintain baseline responding and
to increase motor/performance capacity (especially at
medium to high doses, 15±30 mg/kg). Preliminary
results have shown that unlike cocaine, 3a is hedonically
neutral when administered alone, with a slight increase in
reward at 20 mg/kg (intraperitoneally, IP), the highest
dose tested to date. However, when 5 mg/kg or 10 mg/
kg IP of this derivative were combined with 10 mg/kg
cocaine (IP), an approximate 60% reduction in cocaine-
induced reward enhancement was noted. No changes in
motor/performance capacity were observed, either when
the derivative was administered alone or in combination
The more active analogue 3a was evaluated in the brain
stimulation reward paradigm, a behavioral assay that
allows the measurement of the intrinsic hedonic properties
of compounds separately from the concomitant changes
in the rate of responding. Male rats were implanted with
unipolar electrodes into the lateral hypothalamus and

1446
K. R. C. Prakash et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1443±1446
with cocaine. These ®ndings suggest that 3a may con-
stitute a promising new lead compound that could be
e€ective in reducing cocaine's reinforcing properties.
Although the lack of anity of 3a for SERT may render it
incapable of producing complete cocaine-like reinforcing
e€ects, the mechanism for its antagonistic activity is
uncertain.
P.; Zhang, M.; Johnson, K. M.; Kozikowski, A. P. Med.
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In conclusion, synthetic pathways for the construction of
cocaine analogues bearing one or two ¯uorine atoms at
position 7 of the tropane ring together with their activity
at the DAT are disclosed. While all three compounds are
less potent than their unsubstituted counterpart, com-
pound 3a still retains considerable DAT activity. However,
of considerable interest is the ®nding that this analogue
is capable of a causing a reduction in cocaine-induced
reward enhancement.
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