Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes: Antagonism of cocaine's locomotor stimulant effects

Article abstract of DOI:10.1021/jm000141b

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocain

Full text of DOI:10.1021/jm000141b

J . Med. Chem. 2000, 43, 3283-3294
3283
Ch em ica l Syn th esis a n d P h a r m a cology of 6- a n d 7-Hyd r oxyla ted
2-Ca r bom eth oxy-3-(p-tolyl)tr op a n es: An ta gon ism of Coca in e’s Locom otor
Stim u la n t Effects
Lianyun Zhao,† Kenneth M. J ohnson,‡ Mei Zhang,‡ J udith Flippen-Anderson,§ and Alan P. Kozikowski*,†
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road, NW,
Washington, D.C. 20007-2197, Department of Pharmacology and Toxicology, University of Texas Medical Branch,
Galveston, Texas 77555-1031, and Laboratory for the Structure of Matter, Code 6030, Naval Research Laboratory,
4555 Overlook Avenue, SW, Washington, D.C. 20375-5000
Received March 27, 2000
In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial
agonists, efforts were made to further capitalize on our earlier finding regarding the ability of
a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein,
a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation
of the tropane ring were prepared and tested for their ability to displace [3H]mazindol binding
and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and
7-hydroxylated WIN analogues were readily prepared by use of a classical Willsta¨tter synthesis
to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling
reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of
SmI2 or by catalytic hydrogenation followed by deprotection delivered the final target
compounds. Some of these compounds were found to retain considerable affinity as inhibitors
of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were
less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present
series revealed any substantial potency difference in [3H]mazindol binding versus [3H]DA
uptake, and failed to show “cocaine antagonism” when tested for their ability to prevent cocaine’s
inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b,
which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT,
when tested in vivo, was found capable of attenuating cocaine’s locomotor activity (AD50 ) 94
mg/kg). Taken together, this work provides further support for our hypothesis that drugs that
lack the ability to inhibit transport by all three monoaminergic transporters may exhibit
“partial” cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove
valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal
behavioral paradigms in the search for a cocaine medication.
In tr od u ction
antagonists and partial agonists is being pursued. While
antagonists are more likely to find use in situations of
cocaine overdose, the partial agonist approach may
prove more useful in maintenance programs. Com-
pounds that possess the ability to mimic partially the
effects of cocaine may help to maintain individuals in
treatment programs in a manner analogous to metha-
done, a drug widely used in the treatment of opiate
abuse. Alternatively, or in addition, such “partial ago-
nists” may be able to prevent the effects of cocaine.
Immediate therapies are needed for the treatment of
cocaine abuse worldwide.1 It has been estimated, for
example, that there are at present over 1.5 million
cocaine abusers in the United States alone, and that
approximately one-third of these users are consistent
or hard core users. Undoubtedly, cocaine abuse has a
tremendous negative impact on our society, for it has
been estimated that the health and crime costs associ-
ated with cocaine abuse amount to about 100 billion
dollars per year. Moreover, it has been reported that
approximately one-half million Americans ended up in
hospital emergency rooms last year. Cocaine use figured
into about 28% of these emergency visits, up by 15%
from 1993. At present there are no effective medications
available to treat cocaine addiction, although selegeline
is in phase III trials.1
In pursuit of possible medications we have focused
much of our chemistry efforts on the modification of
cocaine itself, in the belief that appropriate structural
alterations may lead to the desired type of partial
agonist or antagonist activity we seek. In fact, some time
ago we reported the ability of a 7-methoxylated analogue
of pseudococaine to act as weak antagonist of cocaine,
in that it was able to inhibit cocaine’s ability to block
dopamine reuptake.2 Based upon this interesting find-
ing, it became attractive to investigate the activity of
other 6- and 7-substituted cocaine analogues. In par-
ticular, we chose to explore these modifications in the
higher affinity WIN series, in which the 3-position of
To develop agents that might find use in the treat-
ment of cocaine abuse, the search for both cocaine
* To whom correspondence should be addressed. Phone: 202-687-
0686. Fax: 202-687-5065. E-mail: kozikowa@giccs.georgetown.edu.
† Georgetown University Medical Center.
‡ University of Texas Medical Branch.
§ Naval Research Laboratory.
10.1021/jm000141b CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/26/2000

3284 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Zhao et al.
Sch em e 1a
The hydroxytropinone 5 was protected in turn as its
tert-butyldimethylsilyl ether 6 using tert-butyldimeth-
ylsilyl chloride and imidazole in DMF at room temper-
ature for 12 h. This intermediate then was deprotonated
with lithium diisopropylamine (LDA) in the same man-
ner as described by Majewski for tropinone.7 Ketone 6
was treated with LDA in THF at -78 °C, and the
resulting enolate was reacted with methyl cyanoformate
to afford the corresponding racemic carbomethoxylated
derivatives 7 and 8 in 64% yield and in a ratio of 9:7.
The two isomers can be separated by careful flash
column chromatography, and the structure of compound
7, which exists as its enol after removal of the TBDMS
group, was assigned by X-ray analysis.8 The keto esters
7 and 8 served as key intermediates in the synthesis of
6- and 7-hydroxylated WIN type analogues of cocaine.
a
Reagents and conditions: (a) 3 N HCl, rt, 12 h; (b) neutraliza-
tion with 6 N NaOH; (c) NaOAc, CH3NH2‚HCl, rt, 2 d; (d)
TBDMSCl, imidazole, DMF, rt, 12 h; (e) LDA, NC-COOMe, THF,
-78 °C, 1 h.
From this point, a Suzuki coupling protocol was used
to install the tolyl group following a protocol much like
that first reported by Carroll in his synthesis of other
cocaine analogues.9 Hence, the enol triflate 9 was
readily obtained in 73% yield by the addition of N-
phenyltrifluoromethanesulfonimide to a THF solution
of ketone 7 containing sodium bis(trimethylsilyl)amide
at -78 °C (Scheme 2). Reaction of 9 with 4-methylphen-
ylboronic acid, which was prepared from triisopropyl
borate,10 in 1,2-dimethoxyethane using tris(dibenzyl-
ideneacetone)dipalladium(0) as catalyst together with
sodium carbonate and lithium chloride at reflux gave
10 in 98% yield.
the tropane ring bears phenyl in place of cocaine’s
benzoate group. While we have reported to date on the
synthesis of a variety of such 6- and 7-substituted tro-
panes through use of an oxidopyridinium-based cyclo-
addition strategy, we found this method to be cumber-
some in achieving our present objective, which was the
construction of all possible 6- and 7-substituted tropanes
of both chair and boat conformation.3 Herein, we report
on the chemical synthesis and pharmacological charac-
terization of a series of hydoxylated WIN derivatives,
and in one case we also present data showing the ability
of one of these derivatives to antagonize cocaine’s
stimulant effects in a rat locomotor assay. As will
become apparent, the present work provides further
support for our hypothesis that drugs that lack the
ability to inhibit transport by all three monoaminergic
transporters may exhibit only “partial” cocaine-like
properties.4 That is, drugs that are selective for SERT
and NET, or DAT and NET, or SERT and DAT may
have properties that could act either alone or in com-
bination with an “antagonist” to reduce cocaine self-
administration.
Ch em istr y. In terms of developing a chemical ap-
proach to the 6- and 7-substituted WIN analogues, we
initially attempted to use cocaine itself, investigating
the possibility to bring about the remote functionaliza-
tion of this molecule by tethering appropriate function-
ality to the nitrogen atom. Unfortunately, such efforts
did not meet with success. We then modifed our ap-
proach by adapting the route devised by Willsta¨tter
nearly eight decades ago for the synthesis of cocaine
itself.5 The chemical route used to generate the required
6- and 7-hydroxylated tropinones is shown in Scheme
1, and it resembles closely the approach we first used
to prepare the methoxylated pseudococaine derivative
metioned in the Introduction.6
Reduction of 10 with samarium iodide in THF at -78
°C using methanol as the proton source followed by
quenching with acetic acid provided a mixture of the
desired tropanes 11a (22.5%), 12a (32.5%), 13a (17.5%),
and 14a (12.5%) in a total yield of 85%. These products
are readily separable by flash column chromatography.
On the other hand, hydrogenation of 10 over 10% Pd/C
in methanol gives rise to a single product in 80% yield
to which we assign 2R,3R-stereochemistry (compound
14a ) in accordance with literature precedent.11 Under
basic conditions (NaOMe, MeOH, reflux, 24 h; 83%), 14a
is converted to the more stable 2â,3R-isomer 12a .
Compounds 11a and 13a are therefore the other two
isomers. Since 11a epimerizes to 13a with NaOMe in
methanol, 13a must be the 2R,3â-isomer, and 11a the
2â,3â-isomer.
Finally, the TBDMS group of each of the compounds
11a , 12a , and 13a was removed in high yield with
n-Bu4NF in THF at room temperature to give the
corresponding products 11b-13b (87, 99, and 85%,
respectively). However, when compound 14a was treated
with n-Bu4NF in THF, only 12b was obtained as the
product. To avoid this epimerization, which was obvi-
ously a consequence of the basicity of the fluoride anion,
compound 14a was instead deprotected with 48% HF
to afford 7â-hydroxy-3R-(p-tolyl)tropane-2R-carboxylic
acid methyl ester (14b) in 79% yield. The structure of
12b was confirmed by X-ray analysis (Figure 1).
Accordingly, commercially available 2,5-dimethoxy-
2,5-dihydrofuran (1) was stirred in 3 N HCl overnight
at room temperature and then neutralized by the
addition of 6 N NaOH. This mixture was then added to
a solution of acetonedicarboxylic acid, methylamine
hydrochloride, and sodium acetate in water (pH ap-
proximately 4.3). The resulting mixture was then stirred
for 2 days at room temperature. The crude product thus
obtained was recrystallized from 2-propanol to afford
6â-hydroxytropinone (5) as a white solid in 42% yield.
To access the 7R-epimers, the TBDMS group of
compound 10 was removed with n-Bu4NF in THF at
room temperature. The resulting alcohol 15 (91% yield)
was subjected to a Swern oxidation,12 which delivered
the ketone 16 in 97% yield. Reduction of 16 with NaBH4
in methanol gave a 15:1 mixture of the alcohols 17 and
15 in 91% yield. These two compounds were readily

6- and 7-Hydroxylated2-Carbomethoxy-3-(p-tolyl)tropanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3285
Sch em e 2a
a
Reagents and conditions: (a) NaN(TMS)2, PhNTf2, THF, -78 °C to rt, overnight; (b) p-tolylboronic acid, Pd2dba3, Na2CO3, LiCl,
DME, 1 h; (c) SmI2, MeOH, THF, -78 °C, 1 h; (d) H2 (40 psi), 10% Pd/C, MeOH, 12 h; (e) n-Bu4NF, THF, rt, 12 h; (f) 48% HF, CH3CN,
rt, overnight.
F igu r e 1. ORTEP drawings of compounds 17, 19a , 12b, and 24a .
separated by flash chromatography, and the structure
of 17 was established by X-ray analysis (Figure 1).
Attempts at saturating the double bond in the free
alcohol 17 with SmI2 as described above were unsuc-
cessful. Therefore, compound 17 was converted to its
tert-butyldimethylsilyl ether 18, and this intermediate
was reacted with SmI2 in THF/MeOH. Of the reduction
products, only the major isomer 19a was obtained in
pure form in 66% yield while the minor stereoisomers
formed an inseparable mixture. Upon treatment with
NaOMe in MeOH at reflux, approximately 75% of this
mixture was converted to compound 19a . The remaining
products was deprotected with n-Bu4NF in THF, most
of it was transformed into the lactone 20b. Hydrogena-
tion (40 psi) of 18 over 10% Pd/C in methanol gave the
same lactone directly. We conclude that the predomi-
nant isomer among the minor products has 2R,3R-
configuration and that compound 19a has 2â,3R-
configuration. The structure of 19a was subsequently
confirmed by X-ray crystallographic analysis (Figure 1).
Deprotection of 19a with n-Bu4NF in THF provided the
desired compound 19b (Scheme 3).
In the same manner as described above, compound 8
was converted into its enol triflate 21 in 62% yield,
which was coupled with p-tolylboronic acid to produce
the aryl olefin 22 in high yield (Scheme 4). Reduction
1
material exhibited a complex H NMR spectrum and
was not further investigated. If the mixture of minor

3286 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Zhao et al.
Sch em e 3a
a
Reagents and conditions: (a) n-Bu4NF, THF, rt, 12 h; (b) oxalyl chloride, DMSO, -78 °C, 30 min; (c) MeOH, NaBH4, 0 °C-rt, overnight;
(d) TBDMSCl, imidazole, DMF, rt, 12 h; (e) SmI2, MeOH, THF, -78 °C, 1 h; (f) H2 (30 psi), 10% Pd/C, MeOH, 12 h; (g) n-Bu4NF, THF,
rt, 12 h.
Sch em e 4a
a
Reagents and conditions: (a) NaN(TMS)2, PhNTf2, THF, -78 °C to rt, overnight; (b) p-tolylboronic acid, Pd2dba3, Na2CO3, LiCl,
DME, 1 h; (c) SmI2, MeOH, THF, -78 °C, 1 h; (d) H2 (30 psi), 10% Pd/C, MeOH, 12 h; (e) n-Bu4NF, THF, rt, 12 h; (f) 48% HF, CH3CN,
rt, overnight.
of 22 with SmI2 at -78 °C in THF/MeOH gave the
saturated tropane analogues 23a (38%), 24a (48%), and
25a (5%). Intermediate 23a was converted to 25a in
high yield by treatment with NaOMe in MeOH at reflux.
Hydrogenation of 22 over 10% Pd/C, on the other hand,
provided the 2R,3R-isomer 26a exclusively. The struc-
ture of compound 24a was confirmed by X-ray analysis
(Figure 1).13 Finally, the TBDMS group of each of the
compounds 23a , 24a , and 25a was removed in high yield
with n-Bu4NF in THF to give the desired products 23b,
24b, and 25b, respectively. The remaining isomer 26b
was obtained in 92% yield by treatment of 26a with 48%
HF.
Compounds of the 6R-series were prepared, like their
7R-isomers, by stereochemical inversion at the oxygen-
bearing carbon atom. Thus, compound 22 was depro-
tected with n-Bu4NF and the resulting alcohol 27
converted by Swern oxidation to ketone 28, which upon
NaBH4 reduction afforded 27 and its 6R-isomer 29 in a
ratio of 1:5.3. After hydroxyl protection as the silyl ether
30, the double bond was reduced with SmI2 in THF/
MeOH to afford the saturated products 31a (6%), 32a
(69%), and 33a (17%). Hydrogenation of 30 gave the
2R,3R-isomer 34a in 89% yield. Finally, all of these four
intermediates were deprotected with n-Bu4NF or 48%
HF to give the desired products 31b-34b (Scheme 5).
Biology. All of the hydroxylated tropanes described
herein were tested for their ability to displace [3H]mazin-
dol binding. Mazindol has been shown to label the
cocaine binding site on the dopamine transporter of rat
striatal membranes.14 This ligand binds with high
affinity (Kd ) 8.63 ( 0.53 nM) 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
DA, 5-HT, and NE into nerve endings (synaptosomes)
which were prepared from various regions of the rat
brain that are enriched with the particular transporter
under study.15 Comparison of the Ki values for inhibition
of monoamine uptake and mazindol binding was facili-

6- and 7-Hydroxylated2-Carbomethoxy-3-(p-tolyl)tropanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3287
Sch em e 5a
a
Reagents and conditions: (a) n-Bu4NF, THF, rt, 12 h; (b) oxalyl chloride, DMSO, -78 °C, 30 min; (c) NaBH4, MeOH 0 °C-rt, overnight;
(d) TBDMSCl, imidazole, DMF, rt, 12 h; (e) SmI2, MeOH, THF, -78 °C, 1 h; (f) H2 (30 psi), 10% Pd/C, MeOH, 12 h; (g) n-Bu4NF, THF,
rt, 12 h; (h) 48% HF, CH3CN, rt, overnight.
Ta ble 1. Ki Values for 6- and 7-Hydroxylated Tropane Analogues in the Inhibition of [3H]Mazindol Binding and in the Inhibition of
Radiolabeled DA, 5-HT, and NE Uptakea
compound
[3H]mazindol binding
[3H]dopamine uptake
[3H]5-HT uptake
[3H]NE uptake
cocaine
230 ( 16 nM
89.4 nM
423 ( 147 nM
49.8 ( 2.2 nM
39.2 ( 2.6 nM
156 ( 25 nM
5.6 ( 0.2 µM
2.9 ( 0.3 µM
676 ( 43 nM
25 ( 1 µM
155 ( 0.4 nM
108 ( 4 nM
WIN 35065-2b
11b
173 ( 13 nM
37.2 ( 5.2 nM
25.2 ( 2.5 nM
135 ( 15 nM
2.9 ( 0.1 µM
1.4 ( 0.3 µM
540 ( 53 nM
14.5 ( 0.2 µM
126 ( 18 nM
659 ( 39 nM
13.2 ( 3.0 µM
5.1 ( 0.1 µM
1.8 ( 0.1 µM
13.2 ( 1.0 µM
>100 µM
581 ( 57 nM
44.7 ( 9.5 nM
12b
13b
14b
19b
20b
23b
24b
25b
26b
31b
32b
33b
5.9 ( 0.1 µM
60.9 ( 3.5 nM
≈3 µM
≈1 µM
>100 µM
≈300 nM
NT
NT
NT
NT
292 ( 80 nM
996 ( 11 nM
3.1 ( 0.3 µM
1.9 ( 0.3 µM
2.3 ( 0.1 µM
11.7 ( 1.7 µM
97.2 ( 5.6 µM
64 ( 2 µM
6.7 ( 0.4 µM
NT
NT
NT
NT
NT
NT
NT
154 ( 23 nM
NT
NT
NT
NT
NT
NT
NT
34b
54 ( 3 µM
21.0 ( 2.3 nM
35c
51.8 ( 2.1 nM
80.2 ( 1.1 nM
6.3 ( 1.6 nM
a
Ki values are mean ( SE from 2 to 4 independent experiments, each consisting of six drug concentrations (in triplicate) that were
b
selected on the basis of preliminary screening experiments to bracket the approximate IC50 value. WIN 35065-2 is 2â-carbomethoxy-
3â-phenyltropane. c Compound 35 is (1R,5S)-2R-n-propyl-3â-p-tolyltropane.
tated by the use of the same buffer in all assays. The
binding and uptake data are provided in Table 1 along
with comparison data for cocaine.
hydroxy-3R-(3,4-dichlorophenyl) substituted tropane has
both high affinity and selectivity for DAT over the SERT
(IC50 ) 1.2 nM vs 1390 nM). The chemical route used
by Meltzer also makes use of the Willsta¨tter approach
first employed by us in combination with the Suzuki
coupling chemistry.16
As is apparent from the accompanying table, of the
7-hydroxylated tropanes, only 11b and 12b, the former
with the chair conformation and the latter with the boat
conformation, were found to have nanomolar range
potencies in binding and uptake. The chair tropane 11b
is particularly potent, with a Ki of 25 nM in mazindol
binding. The DAT and NET potencies are comparable
(39 and 45 nM) and about 10-fold better than the SERT
potency. On the other hand, the NET potency of 12b is
2-fold better than its DAT potency, while its SERT
potency is in the 6 µM range. Both of the 7â-hydrox-
ylated analogues 13b and 14b, which have an R-orient-
ed ester group, exhibit only micromolar potencies at all
three transporters. The 7R-hydroxylated boat tropane
19b is less active than cocaine in the DAT assay, with
a Ki of about 0.7 µM, with very little activity being
shown by the lactone 20b. During the course of our
work, Meltzer has also reported on the activity of some
7-hydroxylated WIN analogues, finding that a 7â-
Of the 6-hydroxylated compounds, only the tropane
23b of chair conformation had activity in the nanomolar
range (290 nM) at the DAT, while all other 6-hydrox-
ylated derivatives exhibited binding and uptake data
in the micromolar range. The NET activity of 23b is also
good, while this compound shows poor activity at the
SERT. Compound 23b is thus DAT + NET selective.
From the present study one may make the observa-
tion that the mazindol and DA recognition sites are
more tolerable for the 6- and 7-hydroxylated tropanes
that possess a â-oriented hydroxyl group. From a
structural standpoint, this is reasonable, as the nitrogen
atom and N-methyl group that make up the tropane
ring already provide some steric bulk to this face of the
seven-membered carbocycle, and the presence of the
extra hydroxy group causes little further “steric dis-

3288 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Zhao et al.
F igu r e 2. Time course of effects of 12b on horizontal activity
counts/10 min.
turbance”. Also, for the three ligands showing 300 nM
or better DAT potency, their SERT potency is 15- to 50-
fold less. Thus, the 6- or 7-hydroxy group causes a
reduction in activity at the SERT in comparison to the
activity found for cocaine itself or for a 6/7-unsubsituted
WIN analogue. As can be seen from Table 1, cocaine
shows better activity at the SERT than the DAT. Data
are also provided for the WIN analogue 35 bearing an
R-oriented n-propyl group at the 2-position. The DAT
and SERT potencies are comparable in this case,
whereas the compound is more active at the NET.
Unfortunately, based upon a comparison of binding
and uptake data, it appeared that none of our hydrox-
ylated WIN type compounds might act as a cocaine
antagonist by binding to the mazindol site more avidly
than the DA site on DAT. Even when tested as such, in
contrast to what we found previously for the 7R-
methoxylated pseudococaine analogue which possesses
low binding affinity, no functional antagonism was
observed.2a Nonetheless, from our prior experience with
a DAT/NET-selective piperidine-based ligand that shows
no functional antagonism in vitro, but yet is able to
antagonize the effects of cocaine in vivo in locomotor
studies, we chose to scale-up two of the more active of
these compounds, 11b and 12b, to allow for in vivo
studies.2b Compound 12b was chosen based both upon
its DAT potency and its selectivity for the DAT over the
SERT.
Locom otor Stu d y of 11b a n d 12b. Tropanes 11b
and 12b were tested in nonhabituated male Swiss-
Webster mice in the locomotor assay using the standard
operating procedure developed by the Medications De-
velopment Division of the National Institute on Drug
Abuse. Not unexpectantly, the more DAT-potent ligand
11b had an efficacy similar to cocaine when it was tested
alone at a dose range of 3-100 mg/kg, and it was found
to stimulate locomotor activity with an ED50 value of
14.03 mg/kg and a maximal effect/cocaine miximal effect
ratio of 0.88. As a consequence of this activity profile,
11b was not tested for its ability to attenuate cocaine-
induced locomotor activity. On the other hand, the less
DAT-active ligand 12b proved to be more interesting.
Figure 2 shows the average horizontal activity counts/
10 min as a function of time, immediately following
injection of 12b or vehicle. Since 12b did not affect
spontaneous locomotor activity in the dose range finding
experiment, a cocaine interaction study was conducted
next. Figure 3 shows the average horizontal activity
counts/10 min for the different treatment groups as a
function of time, starting 20 min after pretreatment
with 12b. The period of 0-30 min was selected for
F igu r e 3. Interaction between 12b and cocaine on LMA: time
course of effect.
F igu r e 4. Interaction between 12b and cocaine on LMA: dose
response during first 30 min after a 20 min pretreatment.
analysis of the dose-response data because this is the
time period in which cocaine produced its maximal
effects. Figure 4 shows the average horizontal activity
counts/10 min over 30 min as a function of the dose
condition, 20 min after pretreatment with 12b. The bar
above “vehicle” represents the effect of vehicle 20 min
prior to saline injection. The bar above “coc” represents
the effect of vehicle 20 min prior to injection of 20 mg/
kg cocaine. The bars above “3, 10, 30, and 100” represent
the effects of 12b at the designated doses 20 min prior
to injection of 20 mg/kg cocaine. The mean average
horizontal activity counts/10 min on the descending
portion of the dose-effect curve (30 to 100 mg/kg dose
range) for this 30 min period were fit to a linear function
of log dose, and the AD50 (dose attenuating cocaine-
induced stimulation by 50%) was calculated to be 94 mg/
kg. [The ordinate value for the AD50 was calculated
using the mean of the vehicle + 0.9% saline (vehicle)
group as the minimum value, and the mean of the
vehicle plus 20 mg/kg cocaine group as the maximum
value.]
A one-way analysis of variance conducted on log
horizontal activity counts for the 0-30 min time period
indicated a significant overall effect of the treatment
group F(5,42) ) 7.90, p < 0.05; planned comparisons (a
priori contrast) against the cocaine group showed sig-
nificant differences for vehicle and the 100 mg/kg dose
(all p values < 0.05 denoted in Figure 3 with an

6- and 7-Hydroxylated2-Carbomethoxy-3-(p-tolyl)tropanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3289
asterisk). However, as the difference between the “no
effect” dose of 12b at 100 mg/kg alone and the antago-
nism result is only a difference of outcome at the 100
mg/kg dose, it is important that these studies be
extended further. Nonetheless, the present results do
suggest that these hydroxylated tropanes are worthy
of further exploration.
optically pure form using enzymatic methods (PLE) as
previously described.19
Exp er im en ta l Section
Ch em ica l Meth od s. Gen er a l. Diethyl ether was distilled
from phosphorus pentoxide. THF was freshly distilled under
N2 from sodium benzophenone. 1H and 13C NMR spectra were
obtained in CDCl3 with a Varian Unity Inova instrument at
nominal frequencies of 300 and 75 MHz, respectively. 1H
chemical shifts (δ) are reported in ppm downfield from internal
TMS. 13C chemical shifts are referenced to CDCl3 (central peak,
δ ) 77.0 ppm). 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. X-ray data were collected on
a computer controlled Bruker P4 automatic 4-circle diffrac-
tometer. The structures were solved by direct methods and
refined, using all independent data, with full matrix least-
squares on F2 values using the SHELXTL program package.
TLC was performed on Merck silica gel 60F254 glass plates.
Column chromatography (CC) was performed using Merck
silica gel (60-200 mesh).
(()-6â-H yd r oxyt r op a n -3-on e (5). A solution of 2,5-
dimethoxy-2,5-dihydrofuran (2.6 g, 20 mmol) in 3 N HCl (36
mL) was stirred at room temperature for 16 h, neutralized with
6 N NaOH (about 18 mL) and added to a solution of sodium
acetate (13.6 g, 168 mmol), methylamine hydrochloride (2.72
g, 40 mmol), and acetonedicarboxylic acid (5.84 g, 40 mmol)
in water (320 mL). The mixture was left standing for 2 d,
during which time its pH increased from 3.0 to 4.9. K2CO3 and
NaCl (100 g each) were added, and the solution was extracted
with chloroform (4 × 150 mL). The combined chloroform
extracts were dried over MgSO4 and concentrated. The residue
was crystallized from 2-propanol to give the product (1.30 g,
42%) as a white solid: mp 107-108 °C (lit. mp,5f 108-109 °C).
1H NMR δ 4.14 (dd, 1H), 3.61 (m, 1H), 3.38 (d, 1H), 2.78-2.55
(m, 2H), 2.67 (s, 3H), 2.45 (br s, 1H), 2.28-1.92 (m, 4H).
(()-6â-(ter t-Bu tyld im eth ylsilyloxy)tr op a n -3-on e (6). A
solution of 5 (132 mg, 0.85 mmol), imidazole (68 mg, 1.0 mmol),
and tert-butyldimethylsilyl chloride (150 mg, 1.0 mmol) in
DMF (2 mL) was stirred under N2 at room temperature for 32
h. The mixture was diluted with ether, and the solution was
washed with saturated NH4Cl and brine, dried over MgSO4,
and concentrated. CC of the residue (Et2O/Et3N 99:1-19:1)
gave compound 6 (218 mg, 95%) as a clear oil: 1H NMR δ 4.11
(dd, J ) 3.6, 6.3 Hz, 1H), 3.59 (m, 1H), 3.25 (m, 1H), 2.67 (s,
3H), 2.72-2.60 (m, 2H), 2.30-2.00 (m, 4H), 0.88 (s, 9H), 0.23
(s, 6H).
(()-7â-(ter t-Bu t yld im et h ylsilyloxy)-2â-(m et h oxyca r -
bon yl)tr op a n -3-on e (7) a n d (()-6â-(ter t-Bu tyld im eth yl-
silyloxy)-2â-(m eth oxyca r bon yl)tr op a n -3-on e (8). A solu-
tion of diisopropylamine (155 µL, 1.1 mmol) in THF (5 mL)
was cooled to 0 °C, and n-butyllithium (0.48 mL, 2.3 M solution
in hexane, 1.1 mmol) was added. The solution was stirred for
25 min at 0 °C and then cooled to -78 °C. Ketone 6 (269 mg,
1.0 mmol) dissolved in THF (2 mL) was added dropwise over
15 min. The resulting mixture was stirred for 45 min at -78
°C, and then methyl cyanoformate (0.1 mL, 1.3 mmol) was
added dropwise at -78 °C. Stirring was continued at -78 °C
for 20 min. Glacial acetic acid (1.0 mL) and then silver acetate
(168 mg, 1.0 mmol) in glacial acid (1.0 mL) were added at -78
°C. The mixture was warmed to room temperature and stirred
for another 30 min, then concentrated NH4OH was added until
the mixture became clear. The resulting solution was extracted
with CHCl3 (5 × 30 mL). The combined organic extracts were
washed with water and brine and dried over MgSO4. The
solvent was evaporated, and the residue was subjected to CC
(CH2Cl2 saturated with concentrated NH4OH) to give the
â-ketoesters 7 (117 mg, 36%) and 820 (93 mg, 28%). Compound
7: 1H NMR δ 4.13 (dd, J ) 1.5, 6.6 Hz, 1H), 3.78 (s, 3H), 3.67
(br s, 1H), 3.45 (m, 1H), 2.72-2.60 (m, 2H), 2.43 (s, 3H), 2.14-
2.04 (m, 1H), 1.97 (dd, J ) 6.9, 13.8 Hz, 1H), 1.74 (d, J ) 18.6
Hz, 1H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). Compound 8:1H
NMR δ 4.14 (dd, J ) 4.2, 7.5 Hz, 1H), 3.85 (d, J ) 5.7 Hz,
Con clu sion s
The present work details the synthesis of a series of
the 6- and 7-hydroxlated WIN analogues possessing a
boat or chair conformation of the tropane ring. Some of
these compounds retain considerable DAT and NET
potency, with diminished activity at the SERT. While
previously we had found that a methoxylated pseudo-
cocaine analogue was able to antagonize cocaine’s
inhibition of dopamine reuptake, none of the compounds
of the present series revealed any substantial difference
in binding versus uptake, and they failed to show
“cocaine antagonism” when tested for such. However,
one of the hydroxylated WIN analogues, namely 12b,
was tested in vivo and found capable of attenuating
cocaine’s locomotor activity. When the compound was
tested alone at a dose range of 3-100 mg/kg, the
compound was found to have no effect on locomotor
activity. When tested in animals that had been treated
with 20 mg/kg (i.p.), 12b was able to attenuate locomo-
tor activity with an AD50 of 94 mg/kg. In contrast,
locomotor studies using the more DAT-active ligand 11b
revealed this compound to be cocaine-like in its action
(maximal effect/cocaine miximal effect ratio of 0.88).
The present finding suggests that it may prove
valuable to examine the behavioral activity of other 6-
and 7-substituted tropanes in animal behavioral para-
digms in the search for a cocaine medication. Of interest
in this connection is our related finding concerning the
action of 7R-fluoro-3R-(p-fluorophenyl)-2â-propyltro-
pane. This compound was evaluated in the brain
stimulation reward paradigm, a behavioral screen that
allows measuring the intrinsic hedonic properties of
compounds separately from the concomitant changes in
the rate of responding.17 The fluorinated tropane was
found to be unrewarding when administered alone, with
only a slight increase in reward at 20 mg/kg (i.p.), the
highest dose tested to date. However, when 5 mg/kg or
10 mg/kg i.p. of this tropane was combined with 10 mg/
kg cocaine (i.p.), a reduction in cocaine-induced reward-
enhancement (by approximately 60%) was noted. No
changes in motor/performance capacity were observed,
either when the derivative was administered alone or
in combination with cocaine. Like 12b, this fluorinated
tropane also shows better activity at the DAT and NET
versus the SERT (49, 52, and 560, respectively).18
Thus, taken together this work provides further
support for our hypothesis that drugs that lack the
ability to inhibit transport by all three monoaminergic
transporters may exhibit only “partial” cocaine-like
properties. It is our intention to further explore this
hypothesis using other tropanes showing varying levels
of transporter selectivity.
Last, we call attention to the fact that the hydroxlated
tropanes reported herein have been made in racemic
form. Based upon the encouraging behavioral results,
it is our plan to prepare the more potent compounds in

3290 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Zhao et al.
1H), 3.76 (s, 3H), 3.17 (d, J ) 5.4 Hz, 1H), 2.76-2.60 (m, 2H),
2.42 (s, 3H), 2.45-2.20 (m, 1H), 2.12-1.96 (m, 1H), 1.91 (d, J
) 20.7 Hz, 1H), 0.88 (s, 9H), 0.05 (s, 6H).
Hz, 2H), 4.57 (dd, J ) 2.7, 12.0 Hz, 1H), 3.54 (s, 3H), 3.43 (m,
1H), 3.27 (d, J ) 2.4 Hz, 1H), 3.04 (dd, J ) 2.7, 12.0 Hz), 2.90
(dt, J ) 5.7 Hz (d), 12.3 Hz (t), 1H), 2.65 (s, 3H), 2.30 (s, 3H),
2.22-2.10 (m, 2H), 1.82 (t, J ) 12.6 Hz, 1H), 1.56-1.43 (m,
1H), 0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR δ -5.0,
-4.9, 18.0, 21.0, 25.8 (3C), 36.4, 37.1, 39.6, 40.3, 48.2, 51.5,
61.6, 71.6, 73.5, 127.4 (2C), 129.1 (2C), 136.0, 140.6, 173.3.
Compound 14a (5 mg, 12.5%): clear oil; 1H NMR δ 7.08 (d, J
) 8.4 Hz, 2H), 7.04 (d, J ) 8.4 Hz, 2H), 4.64 (dd, J ) 2.7, 6.9
Hz, 1H), 3.63-3.56 (m, 1H), 3.51 (s, 3H), 3.45-3.36 (m, 3H),
2.61 (s, 3H), 2.42-2.28 (m, 1H), 2.29 (s, 3H), 2.04-1.90 (m,
2H), 1.82 (dd, J ) 6.9, 12.3 Hz, 1H), 0.86 (s, 9H), 0.08 (s, 3H),
0.03 (s, 3H); 13C NMR δ -5.0, -4.8, 17.8, 20.8, 25.8 (3C), 35.0,
35.5, 40.3, 41.6, 47.5, 51.2, 60.8, 70.1, 75.5, 127.3 (2C), 128.5
(2C), 135.1, 140.2, 174.0. Anal. (C23H37NO3Si) C, H, N.
Com p ou n d 14a by Hyd r ogen a tion of 10. Compound 10
(10 mg, 25 µmol) was dissolved in absolute MeOH (2 mL) and
hydrogenated over 10% Pd/C at 40 psi for 8 h. TLC showed
almost complete conversion. The catalyst was filtered off over
Celite, and the solvent was evaporated. The residue was
purified by CC (hexane/EtOAc 2:1-1:1) to give 14a (8 mg, 80%)
as a clear oil exhibiting the same spectroscopic data as above.
Gen er a l P r oced u r e for th e Dep r otection of ter t-Bu tyl-
d im eth ylsilyl Eth er s. To a solution of the tert-butyldimeth-
ylsilyl ether in THF was added n-Bu4NF (1.2 equiv, 1 M in
THF) under N2. The mixture was stirred at room temperature
overnight and then concentrated, and the residue was dis-
solved in EtOAc followed by washing with water and brine.
The organic phase was dried over MgSO4 and concentrated,
and the residue was purified by CC (CH2Cl2 saturated with
concentrated NH4OH) to give the free alcohol.
(()-Meth yl 7â-Hyd r oxy-3â-(p-tolyl)tr op a n e-2â-ca r box-
yla te (11b). From the silyl ether 11a (21 mg, 52 µmol), 11b
(13 mg, 87%) was obtained as a white solid: mp 148-149 °C;
1H NMR δ 7.13 (d, J ) 7.8 Hz, 2H), 7.08 (d, J ) 7.8 Hz, 2H),
4.57 (dd, J ) 3.9, 6.3 Hz, 1H), 3.64-3.59 (m, 1H), 3.51 (s, 3H),
3.57-3.49 (m, 1H), 3.04 (t, J ) 3.9 Hz, 1H), 2.78-2.66 (m, 1H),
2.57 (s, 3H), 2.51 (dd, J ) 2.7, 12.6 Hz, 1H), 2.30 (s, 3H), 2.22-
2.12 (m, 2H), 1.93 (br s, 1H), 1.60 (dt, J ) 3.6 Hz (t), 8.4 Hz
(d), 1H); 13C NMR δ 21.0, 32.1, 34.5, 38.3, 42.3, 59.8, 51.2, 63.2,
73.2, 127.0 (2C), 128.7 (2C), 135.4, 139.5, 171.6; MS m/z 289
(M+), 245, 230, 186, 172, 158, 129, 115, 98, 82, 72, 58, 43. Anal.
(C17H23NO3) C, H, N.
(()-Meth yl 7â-(ter t-Bu tyld im eth ylsilyloxy)-8-m eth yl-
3-(tr iflu or om eth a n esu lfon yloxy)-8-a za bicyclo[3.2.1]oct-
2-en e-2-ca r boxyla te (9). Sodium bis(trimethylsilyl)amide (1.0
M in THF, 1.7 mL) was added dropwise to a solution of 7 (462
mg, 1.41 mmol) in THF (5 mL) at -78 °C under N2. After 30
min of stirring, N-phenyltrifluoromethanesulfonimide (555 mg,
1.55 mmol) was added in one portion at -78 °C. The mixture
was allowed to warm to room temperature and was then
stirred overnight. The solvent was removed, the residue was
dissolved in CH2Cl2, and the solution was washed with water
and brine and dried over MgSO4. The organic phase was
concentrated, and the residue was purified by CC (hexane/
EtOAc 8:1-4:1) to afford the product (471 mg, 73%) as an oil:
1H NMR δ 4.28 (dd, J ) 2.1, 6.9 Hz, 1H), 3.83 (s, 3H), 3.53 (m,
1H), 2.78 (dd, J ) 4.2, 18.6 Hz, 1H), 2.20-1.91 (m, 1H), 1.85
(d, J ) 18.6 Hz, 1H), 0.89 (s, 9H), 0.10 (s, 6H).
(()-Meth yl 7â-(ter t-Bu tyld im eth ylsilyloxy)-8-m eth yl-
3-(p-tolyl)-8-azabicyclo[3.2.1]oct-2-en e-2-car boxylate (10).
The triflate 9 (470 mg, 1.02 mmol), p-tolylboronic acid (184
mg, 1.35 mmol), LiCl (95 mg, 2.05 mmol), tris(dibenzylidene-
acetone)dipalladium(0) (41 mg, 45 µmol), and Na2CO3 (0.99
mL, 2.0 M aqueous solution) were combined in 1,2-dimethoxy-
ethane (5 mL) under Ar and heated at reflux for 1 h. The
mixture was cooled to room temperature, filtered through
Celite, and washed with ether. The mixture was basified with
concentrated NH4OH and washed with brine. The organic
layer was dried (MgSO4) and concentrated to dryness. The
residue was purified by CC (hexane/EtOAc 2:1) to afford 10
(405 mg, 98%) as a yellowish solid: mp 45-46 °C; 1H NMR δ
7.13 (d, J ) 7.8 Hz, 2H), 7.02 (d, J ) 7.8 Hz, 2H), 4.36 (dd, J
) 1.8, 6.3 Hz, 1H), 3.77 (s, 1H), 3.55 (s, 3H), 3.51 (m, 1H),
2.72 (dd, J ) 4.2, 18.9 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 3H), 2.23-
2.00 (m, 2H), 1.91 (d, J ) 18.9 Hz, 1H), 0.91 (s, 9H), 0.11 (s,
3H), 0.10 (s, 3H); 13C NMR δ -5.1, -4.6, 18.4, 21.2, 26.0 (3C),
34.8, 35.5, 43.5, 51.3, 57.0, 68.3, 78.8, 126.2, 126.5 (2C), 128.7
(2C), 137.3, 137.8, 144.8, 168.3. Anal. (C23H35NO3Si) C, H, N.
(()-Meth yl 7â-(ter t-Bu tyld im eth ylsilyloxy)-3â-(p-tolyl)-
tr op a n e-2â-ca r boxyla te (11a ), (()-Meth yl 7â-(ter t-Bu tyl-
dim eth ylsilyloxy)-3r-(p-tolyl)tr opan e-2â-car boxylate (12a),
(()-Meth yl 7â-(ter t-Bu tyld im eth ylsilyloxy)-3â-(p-tolyl)-
tr op a n e-2r-ca r boxyla te (13a ), a n d (()-Meth yl 7â-(ter t-
Bu t yld im et h ylsilyloxy)-3r-(p -t olyl)t r op a n e-2r-ca r b ox-
yla te (14a ). To a solution of the aryl olefin 10 (40 mg, 0.10
mmol) in THF (2 mL) at -78 °C under N2 was added SmI2
(4.5 mL, 0.1 M in THF, 0.45 mmol). After stirring for 30 min,
MeOH (anhydrous, 0.5 mL) was added. The mixture was
stirred at -78 °C for another 2 h, then the reaction was
quenched with acetic acid (0.5 mL). The mixture was basified
with NH4OH and extracted with ether, and the organic phase
was dried over MgSO4 and concentrated. The residue was
purified by preparative TLC (hexane/EtOAc 2:1), and the
products 11a -14a were obtained in a total yield of 85%.
Compound 11a (9 mg, 22.5%): white solid, mp 108-109 °C;
1H NMR δ 7.14 (d, J ) 7.8 Hz, 2H), 7.08 (d, J ) 7.8 Hz, 2H),
4.42 (dd, J ) 3.0, 6.9 Hz, 1H), 3.56 (m, 1H), 3.52 (s, 3H), 3.42
(m, 1H), 3.00 (m, 1H), 2.74-2.62 (m, 1H), 2.53 (s, 3H), 2.52-
2.44 (m, 1H), 2.30 (s, 3H), 2.26-2.10 (m, 1H), 2.04 (dd, J )
7.2, 13.8 Hz, 1H), 1.59 (dt, J ) 3.6 Hz (t), 12.3 Hz (d), 1H),
0.92 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR δ -4.8, -4.7,
17.8, 21.0, 25.7 (3C), 33.0, 34.5, 38.8, 43.0, 50.2, 63.5, 77.6,
127.1 (2C), 128.7 (2C), 135.3, 139.6, 171.6. Anal. (C23H37NO3-
Si) C, H, N. Compound 12a (13 mg, 32.5%): yellowish solid,
(()-Meth yl 7â-Hyd r oxy-3r-(p-tolyl)tr op a n e-2â-ca r box-
yla te (12b). From the silyl ether 12 (18 mg, 45 µmol), 12b
(11 mg, 85%) was obtained as a white solid: mp 118-119 °C;
1H NMR δ 7.08 (s, 4H), 4.28 (dd, J ) 3.0, 5.4 Hz, 1H), 3.60 (s,
3H), 3.54-3.35 (m, 2H), 3.27 (s, 1H), 2.70 (s, 3H), 2.58-2.40
(m, 1H), 2.43-2.33 (m, 1H), 2.31 (s, 3H), 2.13-2.04 (m, 2H),
1.36 (dd, J ) 9.3, 14.1 Hz, 1H); 13C NMR δ 21.0, 35.3, 35.6,
39.4, 41.9, 50.7, 51.9, 57.2, 70.3, 79.1, 127.4 (2C), 129.1 (2C),
135.8, 141.3, 175.2; MS m/z 289 (M+), 245, 230, 186, 170, 158,
145, 129, 112, 98, 82, 72, 58, 42. Anal. (C17H23NO3) C, H, N.
(()-Meth yl 7â-Hyd r oxy-3â-(p-tolyl)tr op a n e-2r-ca r box-
yla te (13b). From the silyl ether 13 (17 mg, 42 µmol), 13b
(12 mg, 99%) was obtained as a white solid: mp 187-189 °C;
1H NMR δ 7.12 (d, J ) 8.4 Hz, 2H), 7.08 (d, J ) 8.4 Hz, 2H),
4.55 (dd, J ) 3.6, 6.3 Hz, 1H), 3.54 (s, 3H), 3.46-3.40 (m, 1H),
3.31 (d, J ) 2.7 Hz, 1H), 3.13 (dd, J ) 3.0, 12.0 Hz, 1H), 2.98
(dt, J ) 6.0 Hz (d), 12.3 Hz (t), 1H), 2.68 (s, 3H), 2.30 (s, 3H),
2.45-2.20 (m, 2H), 2.16-1.80 (m, 2H), 1.44-1.34 (m, 1H); 13
C
NMR δ 21.0, 32.0, 35.5, 37.1, 40.9, 44.2, 51.7, 59.5, 70.1, 72.4,
127.2 (2C), 129.2 (2C), 136.1, 140.5, 173.6; MS m/z 289 (M+),
245, 230, 186, 172, 158, 145, 129, 115, 98, 72, 57, 42. Anal.
(C17H23NO3) C, H, N.
1
mp 74-75 °C; H NMR δ 7.08 (s, 4H), 4.31 (dd, J ) 3.0, 6.9
(()-Meth yl 7â-Hyd r oxy-3r-(p-tolyl)tr op a n e-2r-ca r box-
yla te (14b). A THF solution (1.0 mL) of silyl ether 14a (16
mg, 39 µmol) was added to 48% aqueous HF (1.0 mL). After
stirring at room temperature overnight, the mixture was
poured into NH4OH (6.0 mL) and extracted with CHCl3. The
combined extracts were dried, and the solvent was removed.
Purification of the crude product by CC (CH2Cl2 saturated with
concentrated NH4OH) gave 14b (9 mg, 79%) as a white solid:
Hz, 1H), 3.50-3.28 (m, 2H), 3.20 (s, 1H), 2.58 (s, 3H), 2.56-
2.49 (m, 1H), 2.45-2.33 (m, 1H), 2.30 (s, 3H), 2.18-2.06 (m,
1H), 1.98 (dd, J ) 6.9, 13.8 Hz, 1H), 1.29 (m, 1H), 0.87 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR δ -4.9, -4.8, 17.9, 21.0,
25.8 (3C), 36.2, 37.9, 41.9, 42.1, 51.8, 52.3, 60.2, 72.2, 81.5,
127.5 (2C), 129.0 (2C), 135.7, 140.7, 174.7. Anal. (C23H37NO3-
Si) C, H, N. Compound 13a (7 mg, 17.5%): white solid, mp
90-92 °C; 1H NMR δ 7.13 (d, J ) 8.1 Hz, 2H), 7.07 (d, J ) 8.1
1
mp 103-104 °C; H NMR δ 7.09 (d, J ) 8.4 Hz, 2H), 7.04 (d,

6- and 7-Hydroxylated2-Carbomethoxy-3-(p-tolyl)tropanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3291
J ) 8.4 Hz, 2H), 4.73 (dd, J ) 3.0, 6.9 Hz, 1H), 3.72-3.62 (m,
1H), 3.53 (s, 3H), 3.44-3.36 (m, 2H), 3.36-3.29 (m, 1H), 2.62
(s, 3H), 2.52-2.40 (m, 1H), 2.30 (s, 3H), 1.99-1.78 (m, 4H);
13C NMR δ 20.8, 32.1, 35.4, 37.6, 39.2, 42.0, 51.4, 58.9, 68.8,
74.0, 127.2 (2C), 128.7 (2C), 135.2, 140.8, 174.4; MS m/z 289,
(ether/Et3N 99:1) as a white solid in a yield of 66%. The mother
liquor contained predominantly compound 20a together with
a minor component in a ratio of 3:1 (1H NMR). To a solution
of the evaporated mother liquor (20 mg) in dry MeOH (2.0 mL)
was added under N2 30% NaOMe/MeOH (0.1 mL). The mixture
was refluxed for 24 h, cooled to room temperature, and
concentrated. CH2Cl2 and saturated NH4Cl were added, the
phases were separated, and the organic layer was washed with
brine and concentrated. Purification of the residue by TLC
(ether/Et3N 99:1) afforded compound 19a (15 mg, 100%): mp
113-115 °C; 1H NMR δ 7.16 (d, J ) 8.1 Hz, 2H), 7.08 (d, J )
8.1 Hz, 2H), 4.63 (m, 1H), 3.55 (s, 3H), 3.57-3.46 (m, 1H),
3.42-3.17 (m, 3H), 2.73-2.60 (m, 1H), 2.56-2.47 (m, 1H), 2.47
(s, 3H), 2.31 (s, 3H), 1.54-1.41 (m, 2H), 0.95 (s, 9H), 0.13 (s,
3H), 0.10 (s, 3H); 13C NMR δ -5.1, -4.8, 18.0, 21.0, 25.8 (3C),
35.2, 39.1, 40.0, 41.0, 44.1, 51.4, 57.8, 66.1, 71.2, 128.0 (2C),
129.0 (2C), 135.4, 142.7, 176.6. Anal. (C23H37NO3Si) C, H, N.
(()-Meth yl 7r-Hyd r oxy-3r-(p-tolyl)tr op a n e-2â-ca r box-
yla te (19b) was obtained (15 mg, 77%) as an oil in a similar
manner as for the prepation of 11b after purification by CC
(CH2Cl2 saturated with concentrated NH4OH): 1H NMR δ 7.17
(d, J ) 8.1 Hz, 2H), 7.07 (d, J ) 8.1 Hz, 2H), 4.80-4.68 (m,
1H), 3.56 (s, 3H), 3.52-3.34 (m, 3H), 3.22 (t, J ) 7.8 Hz, 1H),
2.80-2.64 (m, 1H), 2.58-2.47 (m, 1H), 2.45 (s, 3H), 1.82 (br s,
1H), 1.45-1.30 (m, 2H); 13C NMR δ 21.0, 35.3, 39.3, 39.9, 40.2,
44.2, 51.8, 58.0, 66.0, 70.8, 128.0 (2C), 129.1 (2C), 135.7, 141.9,
176.2. Anal. (C17H23NO3) C, H, N.
(()-9-Meth yl-3r-(p-tolyl)-6-oxa -9-a za tr icyclo[5.2.1.04,8]-
d eca n -5-on e (20b) was obtained from 18 in 78% yield (9 mg)
by catalytic hydrogenation using a procedure similar to that
for the conversion of 10 to 14, or by SmI2 reduction of 18
followed by treatment of the mixture of minor product stereo-
isomers with n-Bu4NF: 1H NMR δ 7.12 (d, J ) 8.1 Hz, 2H),
7.08 (d, J ) 8.1 Hz, 2H), 5.18 (t, J ) 7.2 Hz, 1H), 4.02 (m,
1H), 3.60-3.38 (m, 2H), 3.00 (dd, J ) 6.9, 8.7 Hz, 1H), 2.58-
2.30 (m, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 1.79 (d, J ) 14.4 Hz,
1H), 1.66 (t, J ) 13.8 Hz, 1H), 1.59 (br s, 1H); 13C NMR δ 21.1,
33.6, 36.0, 38.0, 41.1, 45.4, 59.6, 66.9, 77.2, 81.7, 128.2 (2C),
128.9 (2C), 136.2, 136.5, 176.4; MS m/z 257 (M+), 242, 228,
213, 198, 184, 172, 156, 139, 115, 81, 57, 42.
245, 230, 186, 171, 158, 145, 129, 115, 98, 84, 58. Anal. (C17H23
NO3) C, H, N.
-
(()-Meth yl 7â-Hydr oxy-8-m eth yl-3-(p-tolyl)-8-azabicyclo-
[3.2.1]oct-2-en e-2-ca r boxyla te (15). Compound 10 (40 mg,
0.10 mmol) was deprotected according to the general procedure
to give product 15 (26 mg, 91%) as a white solid: mp 124-
126 °C; 1H NMR δ 7.13 (d, J ) 7.8 Hz, 2H), 7.01 (d, J ) 7.8 H,
2H), 4.29 (dd, J ) 3.6, 4.2 Hz, 1H), 3.74 (s, 1H), 3.53 (s, 3H),
3.44-3.36 (m, 1H), 2.66 (dd, J ) 4.2, 19.2 Hz, 1H), 2.49 (s,
3H), 2.34 (s, 3H), 2.17 (s, 1H), 2.13-2.05 (m, 2H), 1.88 (d, J )
18.9 Hz, 1H); 13C NMR δ 21.2, 33.4, 33.9, 43.1, 51.4, 55.5, 67.7,
77.7, 125.1, 126.5 (2C), 128.8 (2C), 137.4, 137.6, 144.5, 168.4.
Anal. (C17H21NO3) C, H, N.
(()-Meth yl 8-Meth yl-7-oxo-3-(p-tolyl)-8-azabicyclo[3.2.1]-
oct-2-en e-2-ca r boxyla te (16). Oxalyl chloride (122 µL, 1.40
mmol) was dissolved in 5 mL of anhydrous methylene chloride,
and the solution was cooled to -78 °C. Dimethyl sulfoxide (0.40
mL, 2.8 mmol) was added. After 5 min, compound 15 (200 mg,
0.70 mmol) in dry CH2Cl2 (2.0 mL) was added, and stirring
was continued for another 30 min. The reaction was quenched
by adding Et3N (2.0 mL), then the solution was warmed to
room temperature and washed with water, and the aqueous
phase was extracted several times with CH2Cl2. The combined
organic phases were washed with saturated NH4Cl, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the crude product by CC (Et2O/Et3N 99:1-9:1) gave ketone
16 (193 mg, 97%) as a clear oil: 1H NMR δ 7.10 (d, J ) 7.8
Hz, 2H), 6.98 (d, J ) 7.8 Hz, 2H), 4.10 (s, 1H), 3.50 (s, 3H),
3.68-3.44 (m, 2H), 2.96-2.69 (m, 2H), 2.41 (s, 3H), 2.30 (s,
3H), 2.18 (d, J ) 18.3 Hz, 1H), 2.12 (d, J ) 19.2 Hz, 1H); 13C
NMR δ 21.2, 34.2, 35.7, 42.8, 51.7, 55.0, 65.9, 121.9, 126.5 (2C),
128.8 (2C), 137.3, 137.9, 147.7, 166.6, 207.5; MS m/z 257 (M+-
CO), 242, 229, 210, 198, 182, 167, 157, 141, 128, 115, 105, 91,
42. Anal. (C17H19NO3) C, H, N.
(()-Meth yl 7r-Hydr oxy-8-m eth yl-3-(p-tolyl)-8-azabicyclo-
[3.2.1]oct-2-en e-2-ca r boxyla te (17). NaBH4 (47 mg, 1.33
mmol) was added cautiously with stirring to a solution of
ketone 16 (190 mg, 0.67 mmol) in MeOH at 0 °C. The mixture
was allowed to warm to room temperature overnight and then
concentrated. The residue was dissolved in EtOAc (50 mL),
and the solution was washed with water and brine. After
drying over MgSO4 and concentration, the residue was purified
by CC (CH2Cl2 saturated with concentrated NH4OH) to give
the 7R-alcohol 17 (162 mg, 85%) as a white solid together with
compound 15 (11 mg, 6%). Compound 17: mp 113-114 °C;
1H NMR δ 7.13 (d, J ) 7.8 Hz, 2H), 7.06 (d, J ) 7.8 Hz, 2H),
4.65 (m, 1H), 3.88 (d, J ) 5.4 Hz, 1H), 3.48 (s, 3H), 3.31-3.22
(m, 1H), 3.02 (br s, 1H), 2.80 (dd, J ) 3.9, 18.9 Hz, 1H), 2.72-
2.62 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.08 (d, J ) 19.2 Hz,
1H), 1.40 (dd, J ) 4.5, 13.2 Hz, 1H); 13C NMR (CDCl3) δ 21.1,
34.7, 35.1, 40.4, 51.5, 56.5, 64.1, 77.1, 125.3, 126.6 (2C), 128.7
(2C), 137.4, 137.8, 145.0, 170.3. Anal. (C17H21NO3) C, H, N.
(()-Meth yl 7r-(ter t-Bu tyld im eth ylsilyloxy)-8-m eth yl-
3-(p-tolyl)-8-azabicyclo[3.2.1]oct-2-en e-2-car boxylate (18).
Compound 17 (160 mg, 0.56 mmol) was silylated in the same
manner as described for compound 5 and purified by CC
(hexane/EtOAc 2:1-1:1) to furnish the product 18 (89%) as a
clear oil: 1H NMR δ 7.14 (d, J ) 7.8 Hz, 2H), 7.06 (d, J ) 7.8
Hz, 2H), 4.65-4.66 (m, 1H), 4.07 (d, J ) 5.4 Hz, 1H), 3.43 (s,
3H), 3.25 (dd, J ) 4.8, 6.9 Hz, 1H), 2.68-2.50 (m, 2H), 2.40 (s,
3H), 2.36 (s, 3H), 2.12 (d, J ) 18.9 Hz, 1H), 1.36 (dd, J ) 4.8,
12.9 Hz, 1H), 0.83 (s, 3H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR
δ -5.2, -5.0, 18.0, 21.2, 25.7 (3C), 34.6, 35.7, 41.0, 50.9, 56.6,
63.6, 77.6, 126.2, 126.9 (2C), 128.6 (2C), 137.0, 138.7, 144.4,
168.9.
(()-Meth yl 6â-(ter t-Bu tyld im eth ylsilyloxy)-8-m eth yl-
3-(tr iflu or om eth a n esu lfon yloxy)-8-a za bicyclo[3.2.1]oct-
2-en e-2-ca r boxyla te (21). Using a procedure similar to that
for the preparation of 9, triflate 21 (470 mg, 62%) was obtained
after CC (hexane/EtOAc 9:1) as an oil: 1H NMR δ 4.13 (dd, J
) 3.9, 7.5 Hz, 1H), 4.01 (d, J ) 6.0 Hz, 1H), 3.81 (s, 3H), 3.26
(d, J ) 5.4 Hz, 1H), 2.82 (dd, J ) 5.4, 18.9 Hz, 1H), 2.50-2.38
(m, 4H), 2.16-2.04 (m, 1H), 1.99 (d, J ) 18.9 Hz, 1H), 0.88 (s,
9H), 0.07 (s, 6H); 13C NMR δ -4.9, -4.8, 18.2, 25.8 (3C), 29.3,
34.9, 47.5, 52.2, 60.4, 66.4, 78.1, 118.2 (q, J ) 318 Hz), 125.8,
147.4, 163.6.
(()-Meth yl 6â-(ter t-Bu tyld im eth ylsilyloxy)-8-m eth yl-
3-(p-tolyl)-8-azabicyclo[3.2.1]oct-2-en e-2-car boxylate (22).
Using a procedure similar to that for the preparation of 10,
aryl olefin 22 (400 mg, 97%) was obtained after CC (silica gel,
hexane/EtOAc 2:1) as an oil: 1H NMR δ 7.13 (d, J ) 7.8 Hz,
2H), 7.03 (d, J ) 7.8 Hz, 2H), 4.22 (dd, J ) 3.6, 7.2 Hz, 1H),
3.92 (d, J ) 6.0 Hz, 1H), 3.51 (s, 3H), 3.19 (d, J ) 5.1 Hz, 1H),
2.72 (dd, J ) 5.4, 19.5 Hz, 1H), 2.51 (s, 3H), 2.47 (dd, J ) 4.5,
12.6 Hz, 1H), 2.35 (s, 3H), 2.16-2.08 (m, 1H), 2.04 (d, J )
19.2 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR δ -4.7 (2C),
18.3, 21.2, 25.9 (3C), 33.0, 35.7, 47.2, 51.3, 60.9, 66.6, 79.0,
126.6 (2C), 128.7 (2C), 130.5, 137.4, 137.7, 142.2, 168.5.
(()-Meth yl 6â-(ter t-Bu tyld im eth ylsilyloxy)-3â-(p-tolyl)-
tr op a n e-2â-ca r boxyla te (23a ), (()-Meth yl 6â-(ter t-Bu tyl-
dim eth ylsilyloxy)-3r-(p-tolyl)tr opan e-2â-car boxylate (24a),
a n d (()-Met h yl 6â-(ter t-Bu t yld im et h ylsilyloxy)-3â-(p -
tolyl)tr op a n e-2r-ca r boxyla te (25a ) were obtained from 22
using a procedure similar to that for the preparation of 11a -
1
14a . Compound 23a (38 mg, 38%): mp 68-70 °C; H NMR δ
(()-Meth yl 7r-(ter t-Bu tyldim eth ylsilyloxy)-3r-(p-tolyl)-
tr op a n e-2â-ca r boxyla te (19a ). The aryl olefin 18 (40 mg,
0.10 mmol) was treated with SmI2 as described for compound
10. After purification, compound 19a was obtained by CC
7.13 (d, 8.1 Hz, 2H), 7.08 (d, J ) 8.1 Hz, 2H), 4.33 (dd, J )
3.0, 6.9 Hz, 1H), 3.77 (d, J ) 5.4 Hz, 1H), 3.50 (s, 3H), 3.23 (br
s, 1H), 2.86-2.80 (m, 1H), 2.80-2.68 (m, 1H), 2.55 (s, 3H),
2.55-2.44 (m, 1H), 2.30 (s, 3H), 2.25 (dd, J ) 3.0, 6.9 Hz, 1H),

3292 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Zhao et al.
2.17 (dd, J ) 6.9, 12.6 Hz, 1H), 1.76 (dt, J ) 3.9 Hz (t), 12.6
Hz (d), 1H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR δ -4.9 (2C),
17.8, 20.9, 25.7 (3C), 31.2, 34.2, 39.2, 43.1, 51.1, 51.8, 66.4,
70.9, 77.4, 126.9 (2C), 128.7 (2C), 135.3, 139.5, 172.0. Anal.
(C23H37NO3Si) C, H, N. Compound 24a (48 mg, 48%): mp 96-
n-Bu4NF: mp 144-146 °C; 1H NMR δ 7.13 (d, J ) 7.8 Hz,
2H), 7.02 (d, J ) 7.8 Hz, 2H), 4.23-4.10 (m, 1H), 3.93 (d, J )
6.6 Hz, 1H), 3.50 (s, 3H), 3.21 (d, J ) 5.4 Hz, 1H), 2.67 (dd, J
) 5.1, 19.5 Hz, 1H), 2.54 (dd, J ) 7.5, 13.2 Hz, 1H), 2.47 (s,
3H), 2.34 (s, 3H), 2.09 (d, J ) 19.5 Hz, 1H), 2.06-1.98 (m,
1H); 13C NMR δ 21.2, 31.5, 34.3, 51.3, 59.9, 66.0, 77.9, 126.5
(2C), 128.7 (2C), 129.5, 137.4 (2C), 142.4, 168.4.
(()-Meth yl 8-Meth yl-6-oxo-3-(p-tolyl)-8-azabicyclo[3.2.1]-
oct-2-en e-2-ca r boxyla te (28) was prepared from 27 in 97%
(268 mg) yield using a procedure similar to that for the
preparation of 16: 1H NMR δ 7.12 (d, J ) 7.8 Hz, 2H), 7.01
(d, J ) 7.8 Hz, 2H), 4.17 (d, J ) 6.3 Hz, 1H), 3.50 (s, 3H), 3.45
(d, J ) 5.4 Hz, 1H), 2.83 (dd, J ) 6.3, 17.4 Hz, 1H), 2.70 (dd,
J ) 5.7, 19.5 Hz, 1H), 2.53 (s, 3H), 2.52-2.42 (m, 1H), 2.34 (s,
3H), 2.28 (d, J ) 19.5 Hz, 1H); 13C NMR δ 21.1, 29.8, 34.9,
47.7, 51.4, 58.6, 64.5, 126.5 (2C), 128.7 (2C), 129.4, 136.8, 137.7,
144.2, 167.8, 215.5. Anal. (C17H19NO3) C, H, N.
(()-Meth yl 6r-Hydr oxy-8-m eth yl-3-(p-tolyl)-8-azabicyclo-
[3.2.1]oct-2-en e-2-ca r boxyla te (29) was obtained from 28 in
77% yield (202 mg) besides 15% of 27 by NaBH4 reduction as
described in the preparation of compound 17: 1H NMR δ 7.12
(d, J ) 7.8 Hz, 2H), 7.07 (d, J ) 7.8 Hz, 2H), 4.66-4.54 (m,
1H), 3.75 (d, J ) 6.6 Hz, 1H), 3.54 (m, 1H), 3.48 (s, 1H), 3.38
(m, 1H), 2.70 (d, J ) 19.5 Hz, 1H), 2.65-2.53 (m, 1H), 2.46 (s,
3H), 2.34 (s, 3H), 2.46-2.37 (m, 1H), 1.65 (dd, J ) 1.8, 13.2
Hz, 1H); 13C NMR δ 21.1, 26.7, 34.7, 43.5, 51.2, 59.1, 61.6, 72.1,
126.5 (2C), 128.5 (2C), 129.0, 137.2, 137.7, 145.0, 168.6. Anal.
(C17H21NO3) C, H, N.
(()-Meth yl 6r-(ter t-Bu tyld im eth ylsilyloxy)-8-m eth yl-
3-(p-tolyl)-8-a za bicyclo[3.2.1]oct-2-en e-2-ca r boxyla te (30)
was obtained in 85% yield (119 mg) by silylation of 29 in a
similar fashion as described in the preparation of 18: 1H NMR
δ 7.14 (d, J ) 8.1 Hz, 2H), 7.05 (d, J ) 8.1 Hz, 2H), 4.64-4.54
(m, 1H), 3.76 (d, J ) 6.6 Hz, 1H), 3.50 (s, 3H), 3.33 (dd, J )
5.4, 5.7 Hz, 1H), 2.67 (d, J ) 19.2 Hz, 1H), 2.61-2.50 (m, 1H),
2.48 (s, 3H), 2.36 (s, 3H), 1.64 (dd, J ) 5.4, 12.6 Hz, 1H), 0.90
(s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR δ -5.0, -4.8, 18.0,
21.2, 25.9 (3C), 27.5, 35.0, 44.1, 51.2, 59.2, 62.0, 73.2, 126.5
(2C), 128.6 (2C), 129.0, 136.9, 138.6, 146.1, 168.4.
(()-Meth yl 6r-(ter t-Bu tyld im eth ylsilyloxy)-3â-(p-tolyl)-
tr op a n e-2â-ca r boxyla te (31a ), (()-Meth yl 6r-(ter t-Bu tyl-
dim eth ylsilyloxy)-3r-(p-tolyl)tr opan e-2â-car boxylate (32a),
a n d (()-Met h yl 6r-(ter t-Bu t yld im et h ylsilyloxy)-3â-(p -
tolyl)tr op a n e-2r-ca r boxyla te (33a ) were obtained in 6, 69,
and 17.5% yield, respectively, by SmI2 reduction of 30 (297
µmol) using a similar procedure as in the preparation of 11a .
The products were purified by CC (hexane/EtOAc 2:1-1:1).
Compound 31a : 1H NMR δ 7.18 (d, J ) 8.1 Hz, 2H), 7.09 (d,
J ) 8.1 Hz, 2H), 4.74 (m, 1H), 3.50 (s, 3H), 3.50-3.40 (m, 1H),
3.19 (m, 1H), 2.95 (m, 1H), 2.80-2.64 (m, 1H), 2.43 (dt, J )
3.3 Hz (d), 12.9 Hz (t), 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.06 (dt,
J ) 3.6 Hz (t), 12.3 Hz (d), 1H), 1.58 (dd, J ) 3.3, 13.8 Hz,
1H), 0.85 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR δ -5.0,
-4.9, 17.9, 21.0, 25.8 (3C), 28.3, 33.6, 36.3, 42.0, 51.0, 52.4,
64.2, 64.9, 71.7, 127.1 (2C), 128.6 (2C), 134.8, 140.5, 172.6.
Anal. (C23H37NO3Si) C, H, N. Compound 32a : 1H NMR δ 7.16
(d, J ) 8.1 Hz, 2H), 7.08 (d, J ) 8.1 Hz, 2H), 4.59 (m, 1H),
3.56 (s, 3H), 3.36-3.14 (m, 3H), 2.80-2.66 (m, 1H), 2.52 (d, J
) 11.1 Hz, 1H), 2.31 (s, 3H), 2.34-2.25 (m, 1H), 1.99 (dt, J )
8.7 Hz (t), 14.1 Hz (d), 1H), 1.46 (dd, J ) 3.9, 13.5 Hz, 1H),
0.93 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR δ -5.0, -4.8,
18.0, 21.0, 25.8 (3C), 27.1, 36.0, 40.7, 40.8, 51.6, 57.1, 61.9,
62.1, 71.0, 127.9 (2C), 129.0 (2C), 135.6, 142.0, 175.4. Anal.
(C23H37NO3Si) C, H, N. Compound 33a : 1H NMR δ 7.18 (d, J
) 8.1 Hz, 2H), 7.10 (d, J ) 8.1 Hz, 2H), 4.60 (m, 1H), 3.51 (s,
3H), 3.62-3.40 (m, 2H), 3.37-3.24 (m, 1H), 3.18 (m, 1H), 2.62
(s, 3H), 2.46-2.35 (m, 1H), 2.31 (s, 3H), 1.94-1.76 (m, 3H),
0.95 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H); 13C NMR δ -5.1, -4.8,
18.0, 21.1, 29.9 (3C), 28.7, 35.3, 36.1, 37.0, 45.8, 51.4, 61.8,
63.0, 71.7, 127.4 (2C), 129.2 (2C), 135.8, 141.6, 173.9.
1
97 °C; H NMR δ 7.08 (s, 4H), 4.21 (dd, J ) 2.7, 6.6 Hz, 1H),
3.59 (s, 3H), 3.58-3.48 (m, 1H), 3.35 (dd, J ) 9.6, 18.0 Hz,
1H), 3.14 (d, J ) 9.3 Hz, 1H), 2.30 (s, 3H), 2.26-2.14 (m, 1H),
2.08 (dd, J ) 6.9, 13.8 Hz, 1H), 1.42-1.23 (m, 1H), 0.87 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR δ -4.9 (2C), 17.8, 20.9,
25.7 (3C), 34.9, 36.4, 42.1, 42.3, 51.7, 55.3, 63.8, 68.3, 81.5,
127.4 (2C), 129.0 (2C), 135.7, 140.6, 175.0. Compound 25a (5.2
1
mg, 5.2%): mp 195-198 °C; H NMR δ 7.14 (d, J ) 8.1 Hz,
2H), 7.08 (d, J ) 8.1 Hz, 2H), 4.35 (dd, J ) 2.7, 7.5 Hz, 1H),
3.65-3.56 (m, 1H), 3.51 (s, 3H), 3.09 (m, 1H), 3.04 (dd, J )
2.7, 11.7 Hz, 1H), 2.85 (dt, J ) 6.3 Hz (d), 12.0 Hz (t), 1H),
2.66 (s, 3H), 2.39 (dd, J ) 7.5, 14.1 Hz, 1H), 2.30 (s, 3H), 1.97
(ddd, J ) 2.4, 6.9, 13.8 Hz, 1H), 1.79 (dt, J ) 3.0 Hz (d), 13.2
Hz (t), 1H), 1.61 (ddd, J ) 2.7, 6.0, 13.5 Hz, 1H), 0.90 (s, 9H),
0.09 (s, 6H); 13C NMR δ -4.8, -4.7, 18.0, 21.0, 28.8 (3C), 34.3,
36.9, 37.2, 39.4, 48.9, 51.5, 64.2, 69.4, 76.7, 127.4 (2C), 129.1
(2C), 136.0, 140.5, 173.4.
(()-Meth yl 6â-(ter t-Bu tyld im eth ylsilyloxy)-3r-(p-tolyl)-
tr op a n e-2r-ca r boxyla te (26a ). Using a hydrogenation reac-
tion similar to that described for the preparation of 14a , 26a
(15 mg, 76%) was obtained from 22 after CC (hexane/EtOAc
1:1) as an oil: 1H NMR δ 7.10 (d, J ) 8.1 Hz, 2H), 7.05 (d, J
) 8.1 Hz, 2H), 4.03 (dd, J ) 3.3, 7.2 Hz, 1H), 3.78-3.66 (m,
1H), 3.60-3.50 (m, 1H), 3.50-3.38 (m, 4H), 3.09 (d, J ) 5.7
Hz, 1H), 2.62 (s, 3H), 2.29 (s, 3H), 2.42-2.29 (m, 2H), 2.08-
1.96 (m, 1H), 0.80 (s, 9H), -0.06 (s, 3H), -0.07 (s, 3H); 13C
NMR δ -5.0, -4.9, 17.9, 20.8, 25.7 (3C), 32.5, 34.8, 37.0, 41.1,
48.3, 51.1, 62.1, 68.9, 79.0, 127.3 (2C), 128.5 (2C), 135.1, 139.9,
174.0. Anal. (C23H37NO3Si) C, H, N.
(()-Meth yl 6â-Hyd r oxy-3â-(p-tolyl)tr op a n e-2â-ca r box-
yla te (23b), (()-Meth yl 6â-Hyd r oxy-3â-(p-tolyl)tr op a n e-
2r-ca r boxyla te (24b), a n d (()-Meth yl 6â-Hyd r oxy-3r-(p-
tolyl)tr op a n e-2â-ca r boxyla te (25b) were from 23a , 24a , and
25a , respectively, by the General Procedure for desilylation
with n-Bu4NF. Compound 23b (13 mg, 91%): mp 169-171 °C;
1H NMR δ 7.12 (d, J ) 8.4 Hz, 2H), 7.08 (d, J ) 8.4 Hz, 2H),
4.47 (dd, J ) 3.9, 6.0 Hz, 1H), 3.83 (br s, 1H), 3.50 (s, 3H),
3.31 (br s, 1H), 2.83 (m, 1H), 2.75 (m, 1H), 2.58 (s, 3H), 2.51
(dd, J ) 3.3, 12.6 Hz, 1H), 2.30 (s, 3H), 2.27 (m, 2H), 1.86 (br
s, 1H), 1.78 (m, 1H); 13C NMR δ 21.0, 30.7, 38.7, 42.5, 51.2,
51.4, 66.2, 70.6, 77.3, 126.9 (2C), 128.7 (2C), 135.4, 139.5, 172.0.
Anal. (C17H23NO3) C, H, N. Compound 24b (12 mg, 93%): mp
1
102-104 °C; H NMR δ 7.09 (br s, 4H), 4.25 (br s, 1H), 3.64
(m, 1H), 3.61 (s, 3H), 3.45 (m, 1H), 3.20 (d, J ) 9.0 Hz, 1H),
2.68 (s, 3H), 2.47 (d, J ) 9.0 Hz, 1H), 2.35 (m, 1H), 2.18 (m,
2H), 1.98 (br s, 1H), 1.39 (m, 1H); 13C NMR δ 20.9, 33.0, 35.7,
40.6, 42.2, 51.8, 54.3, 62.0, 67.3, 79.9, 127.4 (2C), 129.1 (2C),
135.8, 141.0, 175.1. Anal. (C17H23NO3) C, H, N. Compound 25b
(11 mg, 97%): mp 222-223 °C; 1H NMR δ 7.13 (d, J ) 8.1 Hz,
2H), 7.09 (d, J ) 8.1 Hz, 2H), 4.34 (br d, J ) 6.0 Hz, 1H), 3.58
(br d, J ) 6.9 Hz, 1H), 3.52 (s, 3H), 3.14 (m, 2H), 2.93 (ddd, J
) 6.0, 12.0, 12.6 Hz, 1H), 2.70 (s, 3H), 2.52 (dd, J ) 7.2, 14.1
Hz, 1H), 2.30 (s, 3H), 2.18 (br s, 1H), 1.87 (m, 2H), 1.55 (ddd,
J ) 2.1, 6.0, 13.8 Hz, 1H); 13C NMR δ 21.0, 30.0, 35.4, 37.2,
37.6, 44.6, 51.6, 62.3, 67.8, 75.5, 127.3 (2C), 129.2 (2C), 136.1,
140.6, 173.7. Anal. (C17H23NO3) C, H, N.
(()-Meth yl 6â-Hyd r oxy-3r-(p-tolyl)tr op a n e-2r-ca r box-
yla te (26b) was obtained (13 mg, 90%) from 26a by desilyl-
ation with HF as described for the preparation of 14b: mp
107-109 °C; 1H NMR δ 7.09 (d, J ) 8.4 Hz, 2H), 7.05 (d, J )
8.4 Hz, 2H), 4.09 (dd, J ) 3.0, 7.2 Hz, 1H), 3.74 (m, 1H), 3.63
(m, 1H), 3.48 (s, 3H), 3.46 (m, 1H), 3.17 (m, 1H), 2.68 (s, 3H),
3.63 (dd, J ) 6.9, 14.4 Hz, 1H), 2.46 (m, 1H), 2.32 (br s, 1H),
2.00 (m, 2H); 13C NMR δ 20.8, 30.4, 34.8, 37.1, 38.5, 44.6, 51.3,
60.8, 68.1, 77.2, 127.4 (2C), 128.7 (2C), 135.4, 139.9, 173.9.
Anal. (C17H23NO3) C, H, N.
(()-Meth yl 6r-(ter t-Bu tyldim eth ylsilyloxy)-3r-(p-tolyl)-
tr op a n e-2r-ca r boxyla te (34a ) was obtained (18 mg, 89%)
from 30 by hydrogenation similarly as described for the
preparation of 14a : 1H NMR δ 7.30 (d, J ) 8.1 Hz, 2H), 7.03
(()-Meth yl 6â-Hydr oxy-8-m eth yl-3-(p-tolyl)-8-azabicyclo-
[3.2.1]oct-2-en e-2-ca r boxyla te (27). Compound 27 (279 mg)
was obtained from 22 in 97% yield by desilylation with

6- and 7-Hydroxylated2-Carbomethoxy-3-(p-tolyl)tropanes
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3293
(d, J ) 8.1 Hz, 2H), 4.55 (m, 1H), 3.63-3.44 (m, 2H), 3.34 (dd,
J ) 6.6, 6.9 Hz, 1H), 3.28 (s, 3H), 3.09 (t, J ) 6.9 Hz, 1H),
2.58-2.50 (m, 1H), 2.48 (s, 3H), 2.44-2.33 (m, 1H), 2.28 (s,
3H), 2.14-2.02 (m, 1H), 1.91 (dd, J ) 5.4, 14.4 Hz, 1H), 0.91
(s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR δ -5.0, -4.9, 18.0,
20.9, 23.2, 25.8 (3C), 33.1, 34.2, 38.7, 47.3, 50.6, 59.6, 61.9,
atomic coordinates, bond lengths and angles, anisotropic and
isotropic displacement parameters, and hydrogen coordinates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Refer en ces
71.8, 128.4 (2C), 128.6 (2C), 135.0, 140.9, 173.3. Anal. (C23H37
NO3Si) C, H, N.
-
(1) NIDA Research Report. Cocaine Abuse and Addiction: NIH
Publication No. 99-4342, printed May 1999.
(()-Meth yl 6r-Hyd r oxy-3â-(p-tolyl)tr op a n e-2â-ca r box-
yla te (31b), (()-Meth yl 6r-Hyd r oxy-3r-(p-tolyl)tr op a n e-
2â-ca r boxyla te (32b), a n d (()-Meth yl 6r-Hyd r oxy-3â-(p-
tolyl)tr op a n e-2r-ca r boxyla te (33b) were obtained from 31a ,
32a , and 33a , respectively, by the General Procedure for
desilylation with n-Bu4NF in yields of 85%, 88%, and 82%.
Compound 31b (7.3 mg): 1H NMR δ 7.18 (d, J ) 8.1 Hz, 2H),
7.08 (d, J ) 8.1 Hz, 2H), 4.88 (m, 1H), 3.50 (s, 3H), 3.58-3.40
(m, 1H), 3.28 (m, 1H), 3.00 (m, 1H), 2.80 (ddd, J ) 7.5, 10.5,
14.1 Hz, 1H), 2.52 (dd, J ) 6.3, 12.6 Hz, 1H), 2.34 (s, 3H),
2.99 (s, 3H), 2.08 (dt, J ) 3.9 Hz (t), 12.6 Hz (d), 1H), 1.69 (dd,
J ) 3.9, 14.1 Hz, 1H), 1.64 (s, 1H); 13C NMR δ 21.0, 27.7, 33.5,
35.6, 42.0, 51.1, 52.4, 64.2, 64.4, 71.7, 127.0 (2C), 128.6 (2C),
135.0, 140.1, 172.5. Anal. (C17H23NO3) C, H, N. Compound 32b
(14 mg): mp 123-124 °C; 1H NMR δ 7.19 (d, J ) 7.8 Hz, 2H),
7.11 (d, J ) 7.8 Hz, 2H), 4.73 (m, 1H), 3.59 (s, 3H), 3.43-3.23
(m, 3H), 2.83 (ddd, J ) 7.5, 9.6, 13.8 Hz, 1H), 2.60 (d, J )
10.5 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 2.28-2.16 (m, 1H),
2.14-2.00 (m, 1H), 1.71 (s, 1H), 1.53 (dd, J ) 4.2, 13.8 Hz,
1H); 13C NMR δ 21.0, 27.2, 35.9, 39.8, 40.9, 51.7, 56.7, 61.8,
62.1, 70.8, 127.9, 129.1, 135.8, 141.4, 175.3. Anal. (C17H23NO3)
(2) (a) Simoni, D.; Stoelwinder, J .; Kozikowski, A. P.; J ohnson, K.
M.; Bergmann; J . S.; Ball, R. G. Methoxylation of cocaine reduces
binding affinity and produces compounds of partial agonist
activity: discovery of a weak cocaine “antagonist”. J . Med. Chem.
1993, 36, 3975-3977. (b) Tamiz, A. P.; Zhang, J .; Flippen-
Anderson, J . L.; Zhang, M.; J ohnson, K. M.; Deschaux, O.; Tella,
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analogues of cocaine. 2. Potent dopamine and serotonin reuptake
inhibitors. J . Med. Chem. 2000, 43, 1215-1222.
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J ohnson, K. M.; Kozikowski, A. P. Synthesis and biological
activity of new 6- and 7-substituted 2â-butyl-3-phenyltropanes
as ligands for the DAT. Med. Chem. Res. 1998, 8, 43-58. (b)
Kozikowski, A. P.; Araldi, G. L.; Prakash, K. R. C.; Zhang, M.;
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alkyl and 2â-aryl-3-(substituted phenyl)tropane derivatives:
stereochemical effect of C-3 on affinity and selectivity for
neuronal dopamine and serotonin transporters. J . Med. Chem.
1998, 41, 4973-4982. (c) Smith, M. P.; George, C.; Kozikowski,
A. P. The synthesis of tricyclic cocaine analogues via the 1,3-
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Lett. 1998, 39, 197-200. (d) Smith, M. P.; J ohnson, K. M.; Zhang,
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1
C, H, N. Compound 33b (8.8 mg): mp 153-154 °C; H NMR
δ 7.20 (d, J ) 8.1 Hz, 2H), 7.10 (d, J ) 8.1 Hz, 2H), 4.70 (m,
1H), 3.52 (s, 3H), 3.57-3.44 (m, 1H), 3.40 (dd, J ) 2.4, 7.2 Hz,
1H), 2.25 (dd, J ) 2.7, 12.0 Hz, 1H), 3.21 (dd, J ) 3.0, 6.3 Hz,
1H), 2.63 (s, 3H), 2.47 (ddd, J ) 7.5, 10.5, 13.5 Hz, 1H), 2.31
(s, 3H), 1.93-1.74 (m, 2H), 1.62 (br s, 1H); 13C NMR δ 21.0,
28.3, 34.7, 36.2, 37.0, 46.0, 51.5, 61.8, 62.5, 71.7, 127.4 (2C),
129.1 (2C), 135.9, 141.2, 173.9. Anal. (C17H23NO3) C, H, N.
(()-Meth yl 6r-Hyd r oxy-3r-(p-tolyl)tr op a n e-2r-ca r box-
yla te (34b) was obtained (11 mg, 77%) from 34a by desilyl-
ation with HF as described for the preparation of 14b: 1H
NMR δ 7.17 (d, J ) 8.1 Hz, 2H), 7.08 (d, J ) 8.1 Hz, 2H), 4.63
(m, 1H), 3.66-3.42 (m, 3H), 3.39 (s, 3H), 3.31 (dd, J ) 7.8, 8.1
Hz, 1H), 3.01 (br s, 1H), 2.64-2.49 (m, 2H), 2.41 (s, 3H), 2.31
(s, 3H), 2.08 (dt, J ) 8.1 Hz (t), 14.4 Hz (d), 1H), 1.52 (dd, J )
2.7, 15.0 Hz, 1H); 13C NMR δ 20.8, 23.8, 34.0, 34.2, 40.5, 50.4,
51.5, 60.0, 62.2, 71.4, 128.0 (2C), 128.8 (2C), 135.7, 138.7, 175.5.
Anal. (C17H23NO3) C, H, N.
Locom otor Assa y Meth od . The dose range finding experi-
ment for 12b was conducted according to the MDD locomotor
activity studies standard operating procedure (SOP, Nov. 13,
1992). The study was conducted using 16 Digiscan locomotor
activity testing chambers (40.5 × 40.5 × 30.5 cm). Panels of
infrared beams (16 beams) and corresponding photodetectors
were located in the horizontal direction along the sides of each
activity chamber. Separate groups of eight nonhabituated male
Swiss-Webster mice were injected via the intraperitoneal (i.p.)
route with either vehicle (methylcellulose) or 12b (10 or 100
mg/kg), immediately prior to locomotor activity testing. In all
studies, horizontal activity (interruption of 1 photocell beam)
was measured for 1 h within 10 min sample periods. Testing
was conducted with one mouse per activity chamber.
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Ack n ow led gm en t. We are indebted to the NIH,
National Institute on Drug Abuse (DA10458, DA05867,
and DA09045), and the Office of Naval Research for
their financial support. We also acknowledge NIDA
(NIDA Intramural Research Program, Psychobiology
Section, Drs. D. M. French and J . L. Katz) for the
locomotor studies which were supported by an Intra-
Agency Agreement with the NIDA Division of Treat-
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