Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3β-phenyltropane derivatives

Article abstract of DOI:10.1021/jm960739c

A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [³H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with hi

Full text of DOI:10.1021/jm960739c

858
J . Med. Chem. 1997, 40, 858-863
Syn th esis, Dop a m in e Tr a n sp or ter Affin ity, Dop a m in e Up ta k e In h ibition , a n d
Locom otor Stim u la n t Activity of 2-Su bstitu ted 3â-P h en yltr op a n e Der iva tives
Lifen Xu,† Shreekrishna V. Kelkar,† Stacey A. Lomenzo,† Sari Izenwasser,‡ J onathan L. Katz,‡
Richard H. Kline,‡ and Mark L. Trudell*,†
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, and NIDA Division of Intramural
Research, P.O. Box 5180, Baltimore, Maryland 21224
Received October 23, 1996X
A series of 2â-substituted 3â-phenyltropanes were synthesized as analogs of cocaine and tested
in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake
in rat caudate-putamen tissue. The analogs bound with high affinity (Ki ) 11-22 nM) to the
dopamine transporter. Increased lipophilicity at the â-C(2)-position was found to lead to
increased binding affinity and increased dopamine uptake potency. However, a direct
correlation between clogP values and binding affinity and potency of uptake inhibition was
not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition
relative to the high binding affinity (IC50/Ki ) 10.2). In vivo measurement of stimulated
locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs
(4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately
equipotent with those of cocaine. The structure-activity relationships of this series of cocaine
analogs supports a pharmacophore model in which lipophilic interactions between the â-C(2)-
position of 3â-phenyltropanes and the cocaine binding site on the dopamine transporter lead
to enhanced potency while electrostatic interactions have a nonspecific effect.
In tr od u ction
feature for high-affinity binding. This latter point has
been illustrated by a series of 2â-alkyl-3â-phenyltropane
derivatives prepared and studied by Kozikowski et
al.3,4,10 Additional studies have also demonstrated the
importance of lipophilicity at the â-C(2)-position on DAT
selectivity.9 However, a recent study by Carroll et al.
has demonstrated for a series of 2â-heterocyclic 3â-(4′-
substituted phenyl)tropane derivatives that electrostatic
interactions between the â-C(2)-substituent and the
binding site significantly contributed to the binding
potency of the ligands while lipophilic interactions were
of less importance.6,12
The structural elucidation of the cocaine pharma-
cophore has been the subject of numerous studies.
Derivatives of cocaine (1) and 2-substituted 3-phenyl-
tropanes (2) have proven to be useful probes for explor-
ing the topology of the cocaine binding sites on biogenic
amine transporters.1-12 To date, most of these studies
have focused on the structure-activity relationships
(SAR) of these tropane derivatives at the cocaine binding
site on the dopamine transporter (DAT) due to evidence
which closely links inhibition of dopamine uptake with
the reinforcing properties and other behavioral effects
of cocaine.13-16
It was of interest to explore the apparent dichotomy
of substituent effects on binding affinity. To that end,
a series of 2â-substituted congeners were synthesized
with substituents that varied in lipophilicity. The
biological activity of these compounds was assessed by
examining the affinity at cocaine binding sites on the
DAT, and biological function was assessed by examining
the inhibition of dopamine uptake in vitro as well as
examining the behavioral effects of selected analogs.
Our initial work in this area was to explore the
relative proximal effect of the 2â-carbomethoxy group
of several 3â-phenyltropane derivatives on binding
affinity and [3H]dopamine uptake inhibition.8 From this
study we proposed that a large lipophilic pocket was
present at the binding site capable of accommodating
large substituents at the â-C(2)-position of the ligand.
In addition, we concluded that lipophilicity of substit-
uents at the â-C(2)-position of 3â-phenyltropanes was
important for binding while H-bonding between the
substituent and the binding site was not an essential
Ch em istr y
The 2â-substituted 3â-phenyltropane derivatives were
prepared from 2â-carbomethoxy-3â-phenyltropane (WIN
35,065-2, 2a .)17 Multiple gram quantities of 2a were
readily available from the degradation of cocaine (1)
using an improved synthetic procedure recently reported
from these laboratories.18 As illustrated in Scheme 1,
the ester homologs 4, 5, 7, and 8 as well as the alcohol
derivatives 3, 6, and 9 were prepared by the synthetic
strategy previously reported.8 The ester 2a was reduced
with LiAlH4 to furnish the alcohol 3 in 94% yield.
Swern oxidation of 3 followed by Musamune-Rousch
olefination afforded the R,â-unsaturated ester 4 ste-
reospecifically in 65% overall yield. Hydrogenation (1
atm) of the ester 4 over 10% palladium on carbon gave
* Address correspondence to: Dr. Mark L. Trudell, Department of
Chemistry, University of New Orleans, New Orleans, LA 70148. Tel:
(504) 280-7337. FAX: (504) 280-6860. E-mail: MLTCM@UNO.EDU.
† University of New Orleans.
‡ NIDA Division of Intramural Research.
X Abstract published in Advance ACS Abstracts, February 15, 1997.
S0022-2623(96)00739-X CCC: $14.00 © 1997 American Chemical Society

3â-Phenyltropane Dopamine Uptake Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 859
Sch em e 1a
Ta ble 1. clogP Values, Ki Values for Displacement of Bound
[3H]WIN 35,428 (2b), and IC50 Values for Inhibition of
[3H]Dopamine Uptake
compd
clogP
Ki (nM)a,b
IC50 (nM)a,b
1c
32 ( 5
388 ( 221
33 ( 17
314 ( 222
22 ( 2
405 ( 91
2c
373 ( 100
4
5
6
3.22
3.13
2.71
4.27
4.19
2.23
4.53
6.12
123 ( 65
166 ( 68
64 ( 32
203 ( 77
130 ( 27
159 ( 43
47 ( 15
43 ( 13
23 ( 2
11 ( 1
7
20 ( 2
8d,e
9
30 ( 2
26 ( 3
10
11
28 ( 2
16 ( 2
a
All values are the mean ( SEM of three experiments per-
b
formed in triplicate. All compounds were tested as the HCl salt
unless otherwise noted. c The Ki and IC50 values of these drugs
are reproduced from ref 19 and were collected under identical
conditions. Tested as the fumarate salt. e Uptake inhibition
d
curves were significantly different from linear and as a conse-
quence the IC50 values are only estimates.
Ta ble 2. ED50 Values and Maximal Effects for Stimulation of
Locomotor Activity of Mice and ED50 Values for Substitution
for Cocaine in Rats Trained to Discriminate Cocaine from
Saline
locomotor activity
ED50 valuea
(µmol/kg)
maximal effectb drug discrimination
compd
(counts/10 min) ED50 valuea (µmol/kg)
4
4.74
(3.48-6.47)
11.98
(9.29-15.45)
9.21
(7.06-12.00)
14996 ( 1774
20820 ( 1379
17327 ( 1413
12518 ( 1647
12.78
(10.55-15.47)
12.92
(6.36-26.30)
15.04
(14.70-15.37)
8.74
a
Reagents: (a) LiAlH4, Et2O, 0 °C; (b) (COCl)2, DMSO, Et3N,
6
7
CH2Cl2, -78 °C; (c) (CH3O)2POCH2CO2CH3, i-Pr2NEt, LiCl,
CH3CN, 25 °C; (d) H2, 10% Pd/C, CH3OH; (e) H2, PtO2, CH3OH.
Sch em e 2a
cocaine 20.79
(13.26-32.62)
(6.18-12.18)
a
Parenthetical values represent 95% confidence limits. b Values
represent number of horizontal activity counts per 10 min ( 1
SEM.
ously, cocaine and 2a modeled better for two binding
sites than for one; as a consequence, their high affinity
and low affinity Ki values are given in Table 1.8,19 All
of the higher order analogs (4-11) prepared for this
study were best fit by a single-component model, and
as such, a single Ki value is provided in Table 1.
Selected compounds (4, 6, and 7) were then tested in
vivo and compared with cocaine for their effectiveness
for stimulating locomotor activity. Their ED50 values
for the stimulation of activity were derived as previously
described19 and are reported in Table 2.20 The maximal
stimulant effects and durations of action were also
assessed and compared with those measured for cocaine
(Table 2).20 Drug discrimination studies were conducted
with the selected compounds; rats were trained to
discriminate 10 mg/kg of cocaine (ip) from saline21,22 and
the novel analogs were examined for their potency and
efficacy in substituting for cocaine in test sessions
according to published methods.21
a
Reagents: (a) PhMgBr, Et2O, 0 °C; (b) NH2NH2, KOH, ∆.
the saturated ester 5 in quantitative yield. Reduction
of 5 gave the alcohol 6 which was further converted
sequentially into the R,â-unsaturated ester 7 (89%) and
the saturated ester 8 (95%). Reduction of 4 with LiAlH4
gave the allyl alcohol 9 in 94% yield.
The phenyl ketone 10 was synthesized from 5 by a
1,2-addition reaction of phenylmagnesium bromide. The
deoxygenation of the ketone 10 to furnish the saturated
derivative 11 was achieved by a Wolff-Kishner reaction
(Scheme 2).
Biology
The 2â-substituted 3â-phenyltropanes were tested for
their ability to displace bound [3H]WIN 35,428 (2b) from
rat caudate-putamen tissue.8,19 The Ki values reported
in Table 1 are inhibition constants derived for the
unlabled ligands. In addition, the compounds were
tested for their ability to inhibit uptake of [3H]dopamine
into rat caudate-putamen tissue.8,19 The linear portion
of the inhibition curves were analyzed using analysis
of variance and linear regression techniques, and the
IC50 values are reported in Table 1. As noted previ-
Resu lts a n d Discu ssion
All of the analogs 4-11 exhibited high binding
affinities at DAT, greater than that measured for the
parent ester 2a .8,19 The binding affinities of the ligands
4-11 fit a single-site model better than a two-site
model, with an affinity comparable to the high-affinity
binding components of cocaine and 2a . Within this

860 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
Xu et al.
series of compounds, there was relatively little variation
in binding affinity; the Ki values varied over only an
approximate 3-fold range and exhibited no correlation
with calculated partition coefficients (clogP) determined
for the compounds (Table 1).23
The binding data demonstrate that large, long-chain
substituents at the â-C(2)-position of 3â-aryltropanes
are readily tolerated by the cocaine binding site on the
DAT. This supports the pharmacophore models which
describe the region occupied by the 2â-substituent as a
lipophilic/hydrophobic pocket or cleft in the DAT pro-
tein.8,10 It was interesting to note that although the
magnitudes of the binding affinity (Ki values) were
nearly equal among the different analogs 4-11, there
was somewhat more variance among the IC50 values for
dopamine uptake inhibition. The IC50 values varied
over an approximate 5-fold range of potencies (Table 1).
The unsaturated ester 7 was found to be the least potent
uptake inhibitor of the series, while the alcohol 6 and
the propylphenyl analogs 10 and 11 were 3-4-fold more
potent than 7.
F igu r e 1. The dose-response effect of compounds 4, 5, and
7 on locomotor activity in mice. Ordinates: horizontal activity
counts after drug administration. Abscissae: dose of drug in
µmol/kg (log scale). The point above C represents the effects
of saline vehicle controls. Each point represents the average
effect determined in eight mice. The data shown are from the
first 30 min periods after drug administration, in which the
greatest stimulant effects were obtained.
The high binding affinities and uptake inhibition
potencies of 6 and 11 could not easily be ascribed to the
influence of electrostatic (H-bond) interactions between
the 2â-substituent of the ligands and the binding site
nor could they be directly correlated with lipophilic
parameters, clogP values (Table 1). The potent activity
observed for 6 is believed not to be due to the presence
of the hydrophilic hydroxyl group since the unsaturated
alcohol 9 exhibited diminished activity. Alternatively,
the increased lipophilic character of 6 and 11 relative
to 9 and 10 (clogP values, Table 1), respectively, clearly
resulted in increased binding affinity. In addition, the
saturated alcohol 6 and ester 8 exhibited 2-fold more
potent dopamine uptake inhibition relative to 9 and 7,
respectively, while the more lipophilic 10 and 11 were
equipotent. Comparison of the binding affinities and
dopamine uptake potencies observed for 4-11 (Table
1) suggests that any electrostatic or H-bonding interac-
tion between the hydroxyl of 6 and the binding site is
nonspecific while, in general, it appears that lipophilic
â-C(2)-substituents lead to increased high binding af-
finity and potent dopamine uptake inhibition.
any case, it is apparent that the resolution of the
heterogeneous nature of the cocaine binding site on DAT
cannot be readily achieved by variation of the lipophi-
licity of the 2â-substituent of 3â-phenyltropane deriva-
tives. It is believed that access to different domains of
the cocaine binding site or an alternative binding site
on DAT will require compounds of more diverse
structure.27-30
To further investigate the SAR of 2â-substituents,
three compounds from the series with differing lipophi-
licity and potency were selected for in vivo testing.
Compounds 4, 6, and 7 were believed to be a represen-
tative cross section of the in vitro activity observed for
this series having high binding affinity (Ki ) 11-22 nM)
with moderate, high, and low uptake inhibition, respec-
tively (Table 1). In addition, 7 was of interest because
it has been suggested that compounds which exhibit a
significant difference between potency for inhibition and
DAT binding affinity (IC50/Ki) may produce antagonist-
like effects.28 The ratio calculated for the unsaturated
ester 7 (IC50/Ki ) 10.2) was among the highest ratios
reported for derivatives of cocaine.1
The results of this study are consistent with our
original pharmacophore model8 as well as the model
proposed by Kozikowski et al.10 while a correlation to
the Carroll et al. pharmacophore model based on
enhanced electrostatic interactions was not observed.12
In addition, in contrast to the pharmacophore model
proposed by Crippen et al.,24 it is apparent from the
dopamine uptake inhibition data for 4-11 that the
substituents at the â-C(2)-position do impart significant
activity at the DAT. Moreover, the effects of aqueous
solvation of the ligand does not correlate with the in
vitro activity measured for 4-11.25 If aqueous solvation
effects contributed toward the activity of these com-
pounds, a much greater difference in binding affinity
(Ki) and uptake inhibition (IC50) between 6 and 11 would
be anticipated.
The selected compounds (4, 6, and 7) were tested in
vivo for stimulation of locomotor activity. All three
compounds were found to be locomotor stimulants, with
4 the most potent; approximately 2-3 times more potent
than 6 or 7 and approximately 5 times more potent than
cocaine (Figure 1, Table 2). There were also significant
differences in the maximal stimulation produced by the
compounds. A one-way ANOVA of the maximal effects
produced by each compound was significant (F3,28
)
5.115, p ) 0.006). Posthoc comparisons (Tukey-
Kramer multiple comparisons)31 to determine which of
the maximal effects were significant indicated that 6
had a maximal effect that was significantly greater than
that for cocaine (Table 2), but not different from that of
4 or 7. Neither compound 4 nor 7 was different from
cocaine in terms of maximal stimulation.
No heterogeneous binding could be detected in vitro
for the analogs 4-11.26 This suggests that the com-
pounds despite different lipophilicity at the â-C(2)-
position, either (1) bind to a single site; (2) bind to a
single site at different domains with equal affinity; or
(3) bind at two different sites with equal affinity.26 In
The onset of locomotor stimulant effects of cocaine
was rapid with maximum effects occurring within 10
min after injection (Figure 2). In contrast, for analogs
4, 6, and 7, the maximal stimulation of the locomotor

3â-Phenyltropane Dopamine Uptake Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 861
from the others (see 95% confidence limits in Table 2).
In addition, all of the compounds at least at one dose
produced a complete substitution for the training dose
of cocaine, indicating that they were as effective as
cocaine in producing cocaine-like subjective effects in
animals. Taken together with the stimulation of loco-
motor activity produced by the compounds, these results
indicate that the 2â-substituted analogs each possess a
cocaine-like pharmacology and differ substantially from
cocaine only in their affinity for the DAT and possibly
in their pharmacokinetics. In addition, it is noteworthy
that the IC50/Ki ratios of approximately 10 for 7 did not
confer to it any qualitative or quantitative differences
in agonist activity. This result strongly suggests a lack
of utility of the IC50/Ki ratios as a screen for potential
cocaine antagonists.
F igu r e 2. Time-dependent effects of compounds 4, 6, 7, and
cocaine on locomotor activity in mice. Ordinates: horizontal
activity counts after drug administration expressed as a
percentage of the maximum obtained in any 10 min period
for that dose of the compound. Abscissae: time after injection.
The dashed horizontal line represents the effects of saline
vehicle controls. Each point represents the average effect
determined in eight mice. The data shown are from the dose
producing maximal stimulant effects for each of the com-
pounds; the doses were as follows: 4, 9.1 µmol/kg; 6, 33.3 µmol/
kg; 7, 27.9 µmol/kg; cocaine, 58.8 µmol/kg.
Con clu sion
Despite the difference in the lipophilic character of
the substituents at the â-C(2)-position of the 3â-phen-
yltropanes tested in this study, all the analogs exhibit
homogeneous potent binding affinity. The in vivo
activity of the compounds 4, 6, and 7 exhibited phar-
macological profiles very similar to cocaine. These
results further support a pharmacophore model in which
lipophilic interactions between 2â-substituents and the
cocaine binding site contribute to enhanced potency.
However, while electrostatic (H-bonding) interactions
may be significant at the R-carbon atom of some 2â-
substituents,12 they appear to be of lesser importance
when electron-rich groups are removed from proximity
of the tropane nucleus. In addition, substantial lipo-
philicity was found to lead to prolonged duration of
action of the drug (7). Finally, the heterogeneous nature
of the cocaine binding site was found to be insensitive
to the lipophilicity of substituents at the â-C(2)-position
of the 3â-phenyltropanes. Further studies to address
the heterogeneity of the cocaine binding site are cur-
rently under investigation.
F igu r e 3. Effects of compounds 4, 6, and 7 in rats trained to
discriminate injections of cocaine (10 mg/kg) from equal
volumes of saline. Ordinates: percentage of total responses
on the cocaine-appropriate lever. Abscissae: drug dose in µmol/
kg (log scale). Ordinates: percentage of responses emitted on
the lever on which rats were trained to respond after injections
of cocaine. The lever selection was not considered reliable if
the subject responded at a rate below 0.02 responses per
second, and a point was not plotted on the graph if fewer than
half of the subjects responded above this criterion response
rate. Each point represents the effect in four to six rats.
Exp er im en ta l Section
Melting points were determined on a Mel-Temp II capillary
tube apparatus (uncorrected). Optical rotations were deter-
mined at the sodium D line using an Autopol III automatic
polarimeter. NMR spectra were recorded on a Varian Gemini
300 MHz spectrometer using tetramethylsilane as an internal
standard. All chemicals and reagents were purchased from
Aldrich Chemical Co., Milwaukee, WI, unless otherwise noted.
Tetrahydrofuran and ether were dried by distillation over
sodium/benzophenone. Chromatography refers to flash chro-
matography on silica gel (silica gel 60, E. M. Science, 230-
activity occurred between 10 and 20 min after injection.
Consistent with its duration of action, the effects of
cocaine diminished over the course of the 60 min
session. Diminished activity was also observed over the
session with compounds 4 and 6. However, 7 showed
the least loss of activity during the session (Figure 2).
The source of the prolonged duration of activity is
unclear at this time. However, the lipophilic 2â-side
chain of 7 may enhance the solubility of the drug in fat
tissue and thereby avoid rapid hydrolysis by esterase
enzymes. As a result, slow release of the dissolved drug
from fat tissue may supply sufficient concentrations of
the drug to maintain the observed prolonged activity.
Similar results were observed by Kozikowski et al. for
lipophilic, esterase-resistant analogs.10
400 mesh) and TLC plates (E. M. Science, Kiesel gel 60, F254
,
0.2 mm layer glassback) were purchased from Curtin-Mathe-
son Scientific. Elemental analyses were determined by At-
lantic Microlab Inc., Norcross, GA. The compounds (4-7 and
9-11) were converted into the corresponding hydrochloride
salts by addition of a solution of the base to a saturated
solution of etheral hydrogen chloride (anhydrous). The salt
was collected by filtration and dried under vacuum (56 °C, 0.1
mmHg) for 3 h.
Gen er a l Meth od A. To a stirred suspension of LiAlH4 (76
mg, 2 mmol) in dry Et2O (10 mL) at 0 °C under a nitrogen
atmosphere was added a solution of the ester (2 mmol) in dry
ether (5 mL) dropwise through a syringe, and stirring was
continued overnight at room temperature. The reaction
mixture was cooled to 0 °C, and an aqueous solution of NaOH
was added dropwise. The reaction mixture was filtered and
the residue was washed with ether. The combined filtrate and
Each of the three analogs produced a dose-related
substitution for cocaine in rats trained to discriminate
10 mg/kg doses of cocaine from saline (Figure 3).
Cocaine had the greatest potency which was signifi-
cantly greater than 7, but not significantly different

862 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
Xu et al.
washings were concentrated under reduced pressure to furnish
the alcohol. The alcohol was then purified by chromatography.
Gen er a l Meth od B. To a solution of oxalyl chloride (1.2
mL, 2.0 M solution in CH2Cl2, 2.2 mmol) under nitrogen (-60
°C) was added a solution of DMSO (0.31 mL, 343 mg, 4.4
mmol) in dry CH2Cl2 (1 mL). After 0.5 h, a solution of the
alcohol (2 mmol) in dry CH2Cl2 (3 mL) was added and stirring
was continued for 1 h at -60 °C followed by addition of
triethylamine (1.3 mL, 9.2 mmol) at the same temperature.
The reaction mixture was allowed to warm to room temper-
ature and diluted with water. The organic layer was dried
(Na2SO4), and the solvent was removed under reduced pres-
sure to yield the corresponding aldehyde (95%). The material
was then carried on to the olefination step without further
purification.
Gen er a l Meth od C. To a stirred suspension of lithium
chloride (0.10 g, 2.4 mmol) in dry acetonitrile (10 mL) at room
temperature under a nitrogen atmosphere were added tri-
methyl phosphonoacetate (0.437 g, 2.4 mmol), N,N-diisopro-
pylethylamine (0.26 g, 2.0 mmol), and the aldehyde (2.0 mmol).
The reaction mixture was allowed to stir for 24 h, after which
acetonitrile was removed under reduced pressure and the
residue was diluted with water and extracted with ether (3 ×
40 mL). The combined organic layers were washed with water
and brine and dried (Na2SO4). Removal of the solvent under
reduced pressure and purification of the crude product by
chromatography (ether:triethylamine, 9:1) gave the corre-
sponding unsaturated ester.
complete (TLC) the reaction mixture was filtered and the
solvent was removed under reduced pressure. The residue was
purified by chromatography (SiO2, ether:triethylamine, 90:10)
to afford the ester 11 as an oil (0.60 g, 95%): 1H NMR (CDCl3)
δ 7.42-7.10 (m, 5H, Ph), 3.50 (s, 3H, OCH3), 3.31 (m, 1H),
3.18 (m, 1H), 3.07 (m, 1H), 2.25 (s, 3H, NCH3), 2.22 (m, 1H),
2.11 (m, 3H), 1.98-1.41 (m, 7H), 1.33 (m, 2H), 0.82 (m, 2H);
13C NMR (CDCl3) δ 174.2, 142.4, 128.2, 127.8, 126.1, 65.2, 62.6,
51.4, 45.8, 41.6, 35.9, 33.9, 32.7, 27.1, 26.4, 26.2, 24.7, 24.5;
[R]20 ) -61.8° (c 0.012, CH2Cl2, free base); mp 158-160 °C
D
(fumarate, recrystallized from i-PrOH). Anal. (C20H29NO2‚
C4H4O4) C, H, N.
2â-(3′-Hydr oxypr op-1′-en yl)-3â-ph en yltr opan e (9). Gen-
eral method A from 4 (SiO2, CHCl3:CH3OH, 95:5) gave 9 as
an oil (0.49 g, 95%): 1H NMR (CDCl3) δ 7.40-7.10 (m, 5H,
Ph), 5.80 (dd, J ) 16.0, 6.6 Hz, 1H), 5.25 (m, 1H), 3.85 (m,
2H), 3.30 (m, 1H), 3.14 (m, 2H), 2.15 (m, 4H), 2.25 (s, 3H,
NCH3), 1.80-1.50 (m, 3H); 13C NMR (CDCl3) δ 142.9, 133.1,
130.3, 127.9, 127.7, 125.8, 68.1, 63.7, 62.3, 50.4, 42.1, 36.6, 34.3,
26.6, 25.0; [R]20D ) -93.7° (c 0.007, CH2Cl2, free base); mp 90-
94 °C (HCl salt). Anal. (C17H23NO‚HCl‚1/2H2O) C, H, N.
2â-(3′-P h en yl-3′-oxop r op yl)-3â-p h en yltr op a n e (10). To
a solution of 5 (0.58 g, 2.0 mmol) in dry ether (20 mL) was
added a solution of phenylmagnesium bromide (0.8 mL, 3 M
in ether). The mixture was refluxed for 3 h under an
atmosphere of nitrogen. The reaction mixture was poured in
water (30 mL), and the aqueous layer was extracted with ether
(3 × 50 mL). The combined ether layers were washed with
brine and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue was chromatographed (SiO2,
CHCl3:CH3OH, 9:1) to give 10 as an oil (0.58 g, 87%): 1H NMR
(CDCl3) δ 7.72 (d, J ) 7.2 Hz, 2H), 7.51-7.08 (m, 8H), 3.25
(m, 1H), 3.09 (m, 2H), 2.55 (m, 1H), 2.29 (s, 3H, NCH3), 2.25-
1.87 (m, 4H), 1.80-1.32 (m, 5H), 1.18 (m, 1H); 13C NMR
(CDCl3) δ 200.6, 143.2, 136.7, 132.8, 128.2, 128.1, 127.9, 127.5,
125.8, 65.5, 64.7, 61.9, 45.8, 42.0, 36.0, 33.2, 26.2, 24.7, 23.0;
[R]25D ) -109° (c 0.5, CH2Cl2, free base); mp 238-241 °C (HCl
salt). Anal. (C23H27NO‚HCl‚0.75H2O) C, H, N.
Gen er a l Meth od D. A solution of the unsaturated com-
pound (2.0 mmol) in dry methanol (20 mL) was hydrogenated
(1 atm) over 10% palladium on carbon (15% by w/w). After
the hydrogenation was complete (1H NMR), the reaction
mixture was filtered and the solvent was evaporated under
reduced pressure to give the saturated analog.
2â-(2′-(Me t h oxyca r b on yl)e t h -1′-e n yl)-3â-p h e n ylt r o-
p a n e (4). General method B and C from 38,17 gave 4 as a solid
(0.37 g, 65%): 86-87 °C (free base); 1H NMR (CDCl3) δ 7.22-
7.10 (m, 5H, Ph), 7.10 (d, J ) 15.8 Hz, 1H), 5.40 (d, J ) 15.8
Hz, 1H), 3.60 (s, 3H, OCH3), 3.36 (m, 1H), 3.14 (m, 2H), 2.48
(m, 1H), 2.25 (s, 3H, NCH3), 2.22-2.06 (m, 3H), 1.81-1.62 (m,
3H); 13C NMR (CDCl3) δ 167.2, 150.7, 142.9, 128.7, 128.3,
126.7, 122.1, 67.9, 62.7, 52.2, 51.8, 42.2, 37.3, 35.1, 27.1, 25.5;
2â-(3′-P h en ylp r op yl)-3â-p h en yltr op a n e (11). A solution
of 10 (0.41 g, 1.2 mmol), KOH (1.7 g, 3.6 mmol), and hydrazine
hydrate (1.0 mL) in diethylene glycol (10 mL) was heated to
150 °C overnight. The mixture was allowed to cool to room
temperature and poured in water (150 mL). The aqueous
solution was extracted with ether (5 × 50 mL). The combined
extracts were washed with brine and dried (Na2SO4). The
solvent was removed under reduced pressure, and the residue
was chromatographed (SiO2, CHCl3:CH3OH, 9:1) to afford 11
as an oil (0.26 g, 68%): 1H NMR (CDCl3) δ 7.39-7.01 (m, 10H),
3.29 (s, 1H), 3.18 (m, 1H), 3.05 (m, 1H), 2.42 (m, 2H), 2.31 (s,
3H, NCH3), 2.30-2.01 (m, 3H), 1.78-1.42 (m, 6H), 1.17 (m,
1H), 0.89 (m, 1H); 13C NMR (CDCl3) δ 143.8, 143.2, 128.4,
128.2, 128.0, 127.9, 125.9, 125.5, 65.0, 62.1, 46.4, 42.2, 36.5,
[R]20 ) -107° (c 0.015, CH2Cl2, free base). Anal. (C18H23
-
D
NO2‚HCl‚1/2H2O) C, H, N.
2â-(2′-(Meth oxyca r bon yl)eth yl)-3â-p h en yltr op a n e (5).
General method D from 4 gave 5 as an oil (0.57 g, 99%). 1H
NMR (CDCl3) δ 7.30-7.18 (m, 5H, Ph), 3.57 (s, 3H, OCH3),
3.34 (m, 1H), 3.20 (m, 2H), 2.35 (s, 3H, NCH3), 2.31-2.21 (m,
4H), 2.10-1.51 (m, 6H), 1.30 (m, 1H); 13C NMR (CDCl3) δ
174.3, 143.1, 128.3, 127.7, 126.0, 64.0, 62.1, 51.3, 45.5, 42.1,
36.1, 33.3, 32.4, 26.4, 24.8, 22.9; [R]20D ) -95.6° (c 0.0025, CH2-
Cl2, free base); mp 190-191 °C (HCl salt). Anal. (C18H25NO2‚
HCl‚1/4H2O) C, H, N.
36.3, 33.7, 30.3, 27.4, 26.6, 25.0; [R]25 ) -69.2° (c 0.5, CH2-
D
2â-(3′-Hyd r oxyp r op yl)-3â-p h en yltr op a n e (6). General
method A from 5 (SiO2, CHCl3:CH3OH, 95:5) gave 6 as an oil
(0.51 g, 99%): 1H NMR (CDCl3) δ 7.40-7.08 (m, 5H, Ph), 3.60
(m, 1H), 3.48 (m, 2H), 3.21 (m, 2H), 3.10 (m, 1H), 2.25 (s, 3H,
NCH3), 2.25-2.08 (m, 3H), 1.67 (m, 3H), 1.50 (m, 3H), 1.19
(m, 1H), 0.81 (m, 1H); 13C NMR (CDCl3) δ 143.4, 128.1, 127.8,
125.9, 64.6, 62.8, 62.0, 46.1, 42.1, 36.3, 33.3, 30.8, 26.5, 24.0,
Cl2, free base); mp 235-236 °C (HCl salt). Anal. (C23H29NO‚
HCl) C, H, N.
Ack n ow led gm en t. We are grateful to the National
Institute on Drug Abuse (NIDA First Award R29
DA08055) for the financial support of this research. We
also thank Mr. Brett Heller, Ms. J ulie Haak, and Ms.
Lu Espina for technical assistance.
23.1; [R]20 ) -86.3° (c 0.043, CH2Cl2, free base); mp 205-
D
206 °C (HCl salt). Anal. (C17H25NO‚HCl‚1/4H2O) C, H, N.
2â-(4′-(Me t h oxyca r b on yl)b u t -3′-e n yl)-3â-p h e n ylt r o-
p a n e (7). General methods B and C from 6 (SiO2, ether:
triethylamine, 9:1) gave 7 as an oil (0.55 g, 89%): 1H NMR
(CDCl3) δ 7.21-7.11 (m, 5H, Ph), 6.60 (m, 1H), 5.55 (d, J ) 14
Hz, 1H), 3.51 (s, 3H, OCH3), 3.33 (m, 1H), 3.20 (m, 1H), 3.08
(m, 1H), 2.39 (s, 3H, NCH3), 2.31-1.90 (m, 5H), 1.61 (m, 4H),
1.50 (m, 1H), 0.95 (m, 1H); 13C NMR (CDCl3) δ 166.9, 149.4,
142.3, 128.2, 127.7, 126.1, 120.8, 65.1, 62.4, 51.2, 45.3, 41.7,
35.8, 32.6, 30.2, 26.2, 25.5, 24.4; [R]20D ) -58.0° (c 0.056, CH2-
Cl3, free base); mp 130-133 °C (HCl salt). Anal. (C20H27NO2‚
HCl‚1/2H2O) C, H, N.
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