Synthesis and transporter binding properties of 2,3-diphenyltropane stereoisomers. Comparison to 3β-phenyltropane-2β-carboxylic acid esters

Article abstract of DOI:10.1021/jm960703k

2β,3β-Diphenyl-(5), 2α,3α-diphenyl-(6), and 2α,3β-diphenyltropane (3) as well as 2,3-diphenyltrop-2-ene (4) were prepared in racemic form and assayed for inhibition of radioligand binding at the dopamine (DA), serotonin (5-HT), and norepinephrine (NE) tra

Full text of DOI:10.1021/jm960703k

J . Med. Chem. 1997, 40, 1247-1251
1247
Syn th esis a n d Tr a n sp or ter Bin d in g P r op er ties of 2,3-Dip h en yltr op a n e
Ster eoisom er s. Com p a r ison to 3â-P h en yltr op a n e-2â-ca r boxylic Acid Ester s
An-Chih Chang,† J ason P. Burgess,† S. Wayne Mascarella,† Philip Abraham,† Michael J . Kuhar,‡ and
F. Ivy Carroll*,†
Chemistry and Life Sciences, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709,
and Neuroscience Branch, National Institute on Drug Abuse (NIDA) Addiction Research Center, P.O. Box 5180,
Baltimore, Maryland 21224
Received October 8, 1996X
2â,3â-Diphenyl-(5), 2R,3R-diphenyl-(6), and 2R,3â-diphenyltropane (3) as well as 2,3-diphen-
yltrop-2-ene (4) were prepared in racemic form and assayed for inhibition of radioligand binding
at the dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters. Among all
three transporters, compounds 4-6 bound the DA transporter with the highest affinity. The
2â,3â-diphenyltropane (5) bound the DA transporter with an IC50 value (28 nM) almost identical
to that of 3â-phenyltropane-2â-carboxylic acid methyl ester (WIN 35,065-2) and has much
greater selectivity relative to binding to the serotonin transporter. A comparison of the
radioligand data from this study to radioligand data obtained on other WIN 35,065-2 analogs
suggests that hydrophobicity of the C-2 substituent of some analogs of the WIN 35,065-2 class
may be an important contributing factor to binding at the DA transporter.
Because of its powerful reinforcing properties, (R)-
(-)-cocaine (1) has great abuse potential, and the level
of its abuse has reached epidemic proportions in the
recent years. While cocaine inhibits the presynaptic
uptake of dopamine (DA), serotonin (5-HT), and nor-
epinephrine (NE), evidence suggests that cocaine bind-
ing to the dopamine transporter and consequently the
inhibition of dopamine uptake may be responsible for
the reinforcing and locomotor properties of cocaine.1-5
These findings have prompted extensive studies aimed
at a better understanding of cocaine’s mechanism of
action and the structural requirements of the cocaine
binding site on the dopamine transporter.
Extensive structure-activity relationship (SAR) stud-
ies of cocaine (1) and the WIN 35,065-2 (2a ) classes of
compounds have identified structural features required
for potency and selectivity for inhibition of radioligand
binding at the dopamine transporter which include an
aromatic ring at the 3-position, the tropane nitrogen,
and the N-substituent.6-11 However, the requirements
for the 2-substituent have been less well-defined. Re-
cent studies have shown that the 2â-carbomethoxy
group found in cocaine (1) and WIN 35,065-2 analogs
(2) can be replaced by ketones,12 heterocycles,13,14
amides,15 alkyl groups,16,17 and olefins18 and still retain
high potency for the dopamine transporter.
In the present study, we investigate the effect of
replacement of the 2â-carbomethoxy group of WIN-35,-
065-2 with a phenyl group on dopamine transporter
binding. Various stereoisomers of (()-2,3-diphenyltro-
panes (3-6) were synthesized and evaluated in com-
petitive binding assays to determine their affinities for
the DA, 5-HT, and NE transporters.
produced intermediates 8 (Scheme 1). Reduction of the
ethoxycarbonyl group in compound 8 with lithium
aluminum hydride yielded target compound 3. Alter-
natively, intermediate 8 was dehydrated to produce the
tropene 9, which was found to readily undergo a
photochemical reaction, presumably cyclizing to form a
phenanthrene derivative. However, compound 9 could
be reduced to target compound 4 or hydrogenated before
lithium aluminum hydride reduction to generate com-
pounds 10 and 11. Thus, the routes in Scheme 1
resulted in the synthesis of 2R,3â-diphenyl (3), 2â,3â-
diphenyl (5), and 2R,3R-diphenyltropanes (6) as well as
2,3-diphenyltrop-2-ene (4). Attempts to prepare 2â,3R-
diphenyltropane were unsuccessful.
Ch em istr y
The target compounds were synthesized as racemates
from intermediate (()-7, which was prepared in five
steps from 3-tropinone via a reported synthesis.19,20
Treatment of (()-7 with phenylmagnesium bromide
The structures and stereochemical assignments for
1
the compounds were determined using H, 13C NMR,
2D COSY,21,22 NOESY,23 and HMQC24 spectral analysis.
The stereochemical assignments for compounds 3, 5,
and 6 were established using vicinal coupling constants
obtained from 1H NMR spectra supplemented with
through-space interactions obtained from 2D NOESY
† Research Triangle Institute.
‡ NIDA Addiction Research Center.
X Abstract published in Advance ACS Abstracts, March 15, 1997.
S0022-2623(96)00703-0 CCC: $14.00 © 1997 American Chemical Society

1248 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Chang et al.
Sch em e 1
Ta ble 1. Binding Affinities of 3-6 at the DA, 5-HT, and NE Transporters
IC50 (nM)
compd
R1
R2
R3
R4
DA
5-HT
NE
cocaine (1)a
89 ( 4.8
23 ( 5
1050 ( 89
3300 ( 290
920 ( 73
2a a
CO2CH3
OH
H
Ph
Ph
Ph
Ph
H
H
H
1960 ( 61
(()-3
Ph
Ph
H
2860 ( 290
550 ( 43
28 ( 1.9
37200 ( 2410
47800 ( 4910
34700 ( 3950
18600 ( 1880
>175000
(()-4 (2-tropene)
(()-5
21400 ( 1630
2670 ( 6270
2770 ( 280
Ph
H
H
Ph
(()-6
Ph
1270 ( 120
a
The IC50 values are from ref 15.
Ta ble 2. NMR Characteristics of 3, 5, and 6
spectra. Analysis of the dihedral angles in substititued
3-phenyltropanes in the chair conformation have shown
that a 1,2 diaxial relationship between two protons
produces a dihedral angle of approximately 180° and
therefore, using the Karplus relationship,25 gives a large
vicinal coupling constant, whereas a 1,2 axial- equato-
rial relationship produces a dihedral angle of around
45° and, therefore, gave a medium vicinal coupling
constant.13 The large diaxial coupling constant (J 3)
12.5 Hz) between H3 and H4â (Table 2) of compound 3
showed that this compound possessed a 3â-phenyl
group. Since H4â is axial, H3 must also be axial, and
the 3-phenyl is equatorial. The 2-position is disubsti-
tuted; thus, information cannot be gained from analysis
of coupling constants. However, the NOESY spectrum
of compound 3 reveals an interaction between the
J 23 J 34â
characteristic
compd R2â R2R R3â R3R (Hz) (Hz) NOE interactions
(()-3 OH Ph
Ph
Ph
H
H
H
Ph
12.5 H7-Ph2R
(()-5 Ph
(()-6
H
6.6 13.0 H3R-H6, H2R-H7
H
Ph
8.0
8.0 H2-H4â, H2â-NMe
2-phenyl and H7. This shows that the 2-phenyl group
is equatorial. In compound 5 the large diaxial coupling
constant (J 3 ) 13.0 Hz) between H3 and H4â shows that
H3 is axial. Since H3 is axial, the medium coupling

2,3-Diphenyltropane Stereoisomers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8 1249
constant (J 3 ) 6.6 Hz) between H3 and H2, character-
istic of an axial-equatorial relationship, fixes H2 as
equatorial. Further confirmation of this stereochemis-
try was obtained from the NOESY spectrum which
shows an interaction between H2R and H7and between
H3R and H6. These interactions also validate the
assumption of the chair conformer. In compound 6 the
medium coupling constant (J 3 ) 8.0 Hz) reveals an
axial-equatorial relationship between H3 and H4â.
Therefore, H3 must be equatorial. Neither the coupling
of H2 to H3 nor to H1 is diagnostic of the stereochem-
istry of H2. However, the NOESY spectrum of 6 shows
an interaction between H2 and H4â which is possible
only if H2 is axial. This interaction also eliminates the
possibility of the boat conformation in compound 6.
techniques to range from 4.2 Å (â epimer) to 5.1 Å (R
epimer). These 2-phenyl derivatives therefore mimic
the spatial arrangement seen in calculated low-energy
conformations of dopamine (3.3-5.1 Å) and in 5-HT and
NE pharmacophore geometries (ca. 5.1 Å).26,27
A possible explanation for the wide range of substit-
uents that can be accommodated at the C-2 position of
the tropanes is the existence of several different binding
modes for the C-2 group. While the â-orientation of the
C-2 group is required, C-2 substituents may be capable
of interacting with the DA transporter binding site via
an electrostatic/hydrogen-bonding or hydrophobic pro-
cess depending on the nature of the C-2 group. More-
over, the results obtained with cocaine analogues bear-
ing aromatic heterocycles at the C-2 position13,14 suggest
that the electrostatic interactions predominate over
hydrophobic interactions when both types of interactions
are possible for the 2â-substituent. For cocaine ana-
logues bearing 2â-heterocycles, a high correlation was
found between molecular electrostatic potential (not
hydrophobicity) and binding potency.13 The QSAR
developed for the 2â-heterocycles also strongly sug-
gested that the role of the 2-substituents involved
electrostatic forces other than hydrogen bonding. Con-
sistent with this are these new 2â-phenyl analogs which
lack hydrogen-bonding functionality at the 2-position
but retain significant binding potency.
Preparation of 5 in optically pure form via either
resolution or stereoselective synthesis and substitutions
of the 2- and 3-phenyl rings should improve both binding
affinity and selectivity for the dopamine transporter.
Since 4′-substitution of the 3â-phenyl ring of WIN
35,065-2 analogs significantly enhances the biological
activity of cocaine analogues;6-18 similar changes to 5
would be expected to enhance potency. For example,
since changing the 3â-phenyl group of 2a to a 4′-
chlorophenyl 2b resulted in a 23-fold increase in po-
tency,7 similar changes in the optical isomer of 5 would
be expected to provide analogs with greater potency at
the DAT. Also, in direct analogy to modifications that
have been performed on the 3â-phenyl group, similar
modifications of the 2â-phenyl ring will be undertaken
to study the effect of altering the electrostatic and steric
properties of this substituent and thereafter allow the
development of an expanded QSAR correlating the
structural variation and binding potency of the various
2â-heterocyclic and 2â-aryl-substituted analogs.
Biology
The binding affinities of the compounds for dopamine,
serotonin, and norepinephrine transporters were deter-
mined via competitive binding assays using previously
reported procedures.14 The radioligands used were 0.5
nM [3H]WIN35,428 for the DA transporter, 0.2 nM [3H]-
paroxetine for the 5-HT transporter, and 0.5 nM [3H]-
nisoxetine for the NE transporter.
The binding affinities of compounds 1, 2a , and 3-6
are listed in Table 1. The 2â,3â-diphenyl isomer 5 with
an IC50 value of 28 nM was the most potent at the DA
transporter. Moreover, this compound is highly selec-
tive for the DA transporter relative to the serotonin
transporter. The 2R,3â-diphenyl isomer 3 and the
2R,3R-diphenyl isomer 6 were found to have poor affinity
for the cocaine binding site on the DA transporter, with
IC50 values of 2.9 and 1.3 µM, respectively.
Discu ssion
The presently reported results provide additional
information that a 2â-carbomethoxy group is not neces-
sary for high-affinity binding at the cocaine binding site
on the DA transporter. Furthermore, the present
results indicate that a phenyl ring can substitute for
the 2â-carbomethoxy group in WIN 35,065-2 without
loss in binding affinity. The high potency of the 2â,3â
isomer relative to the 2R,3â and 2R,3R isomers is also
consistent with other cocaine analogues bearing sub-
stituents at both C-2 and C-3 positions of the other
tropane systems.6-18
In view of the racemic nature of the compounds
reported in this study, it can be concluded that (()-5
and (R)-2a bind the DA transporter with equal affinity.
However, 5 exhibits much greater selectivity for the DA
transporter over the 5-HT and at least equal selectivity
over the NE transporters relative to 2a . This is
consistent with previous studies which found that 3â-
(4′-methylphenyl)- and 3â-(4′-chlorophenyl)tropane-2â-
carboxylic acids phenyl esters (2c and 2d , respectively)
retained DA transporter binding affinity similar to their
corresponding methyl esters while showing significantly
improved DA transporter selectivity.15 These results
suggest that an aromatic ring C-2 substituent may be
an important contributing factor to binding at the DA
transporter. Aryl substitution at the 2-position places
the aromatic group two carbons away from the basic
tropane nitrogen. The resulting nitrogen atom-to-
phenyl ring distance (measured from the centroid of the
phenyl ring) can be calculated using molecular modeling
Exp er im en ta l Section
Elemental analyses were conducted by Atlantic Microlab,
Inc. in Norcross, GA. [3H]-3â-(p-Fluorophenyl)tropane-2â-
carboxylic acid methyl ester ([3H]WIN 35,428) and [3H]-
paroxetine were purchased from DuPont-New England Nuclear
(Boston, MA). [3H]Nisoxetine was purchased from American
Radiolabeled Chemicals, Inc. (St. Louis, MO). When anhy-
drous conditions were required, solvents were distilled and
dried by standard techniques immediately prior to use. All
air- and moisture-sensitive reactions were conducted under a
prepurified nitrogen atmosphere in oven-dried glassware at
115 °C. Routine NMR spectra were obtained on a Bruker AM-
250 spectrometer. COSY, NOESY, and HMQC spectra were
recorded on a Bruker AMX-500 spectrometer operating at
500.13 MHz for 1H using a Bruker 5 mm inverse detect
broadband probe. The double quantum filtered phase-sensi-
tive COSY21,22 and NOESY28 were acquired as 1024 × 512 data
points with a spectral width of 4800 Hz in both dimensions.
The data were apodized with a squared sine function and zero
filled to 2K × 2K data points prior to Fourier transformation.

1250 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Chang et al.
NOESY spectra were obtained with a 1200 ms mixing time
and a recycle delay of 4 s. Heteronuclear multiple quantum
correlation (HMQC)24 spectra were acquired as 1024 × 256
data points with a spectral width of 4800 Hz in F2 and 24375
Hz in F1. An average coupling constant of 145 Hz was used
to optimize 1/J CH delays. The data were apodized with a
squared sine function and zero filled to 2048 × 512 data points
prior to Fourier transformation.
free base) δ 14.87, 30.59 (d), 33.81 (d), 38.77 (d), 52.95, 58.62,
61.08, 126.46, 126.63, 127.79, 128.02, 128.96, 129.49, 130.74
(d), 139.84, 140.83, 141.45 (d), 154.93; MS (EI) m/ z 333.40.
Anal. (C22H23NO2) C, H, N.
Note: Compound 9 readily undergoes a photochemical
reaction when exposed to UV radiation.
(()-2,3-Dip h en yl-tr op -2-en e (4). Compound 4 was pre-
pared from 9 (0.11 g, 0.34 mmol) and 1.0 M LAH in Et2O (1.01
mL, 1.01 mmol) using conditions similar to those for the
preparation of 3. The crude product was purified by flash
column chromatography eluting with CHCl3/5% MeOH/0.5%
NH4OH. The free base was converted to the HCl salt with
1.0 M HCl in Et2O to yield 0.106 g of 4‚HCl (100%) after
evaporation from a mixture of hexane and CH2Cl2: mp (HCl
salt) 102 °C dec; 1H NMR (CDCl3, free base) δ 1.70-2.40
(complex, 5H), 2.58 (s, 3H, NCH3), 2.78 (dd, J ) 18.0 and 4.0
Hz, 1H, H4), 3.44 (m, 1H, CH), 3.65 (m, 1H, CH), 6.90-7.20
(m, 10H, aromatic); 13C NMR (CDCl3, free base) δ 30.35, 33.59,
36.17, 58.19, 65.21, 126.25, 127.78, 127.94, 128.88, 129.30,
130.13, 138.54, 141.22 (not all sp2 carbons were observed due
to overlap of peaks); MS (EI) m/ z 275.30. Anal. (C20H21N‚
HCl‚0.75H2O) C, H, N.
(()-8-(Eth oxyca r bon yl)-2â,3â-d ip h en yln or tr op a n e (10)
a n d (()-8-(E t h oxyca r bon yl)-2r,3r-d ip h en yln or t r op a n e
(11). A mixture of (()-9 (0.06 g, 0.18 mmol) and 10% Pd/C
(31 mg) in MeOH (4 mL) was hydrogenated at room temper-
ature under 50 psi. The hydrogen pressure was raised to 50
psi as needed. After 5 days, the mixture was filtered through
Celite, and the Pd/C was washed with MeOH (120 mL). The
combined filtrate was evaporated to dryness to yield a mixture
of (()-10 and (()-11, which were separated by radial PLC on
1 mm silica gel plates eluting with hexane/10% Et2O to yield
the more polar (()-10 (37.5 mg, 62%) and the more nonpolar
(()-11 (18.7 mg, 31%).
(()-8-(Eth oxycar bon yl)-2â,3â-diph en yln or tr opan e (10):
1H NMR (CDCl3) δ 0.84-1.25 (2 br s, 3H, CH3), 1.82-2.67
(complex, 6H, 3 CH2), 3.17 (br s, 1H, CH), 3.58-3.78 (complex,
3H, 1 CH and OCH2), 4.50 (br s, 1H, CH), 4.74 (br s, 1H, CH),
6.99-7.11 (m, 10H, aromatic). Anal. (C22H25NO2‚0.25H2O) C,
H, N.
(()-8-(Eth oxycar bon yl)-2r,3r-diph en yln or tr opan e (11):
1H NMR (CDCl3) δ 1.30 (t, J ) 7.0 Hz, 3H, CH3), 1.59-2.71
(complex, 6H, 3 CH2), 3.52 (m, 1H, CH), 4.03 (m, 1H, CH),
4.20 (q, J ) 7.0 Hz, 2H, OCH2), 4.49 (m, 1H, CH), 4.68 (m,
1H, CH), 6.96-7.21 (m, 10H, aromatic). Anal. (C22H25NO2)
C, H, N.
(()-8-(Eth oxycar bon yl)-2r-ph en yl-3â-ph en yln or tr opan -
2â-ol (8). With stirring at -20 °C (salt-ice), 3.0 M PhMgBr
in Et2O (1.9 mL, 5.8 mmol) was added dropwise over 4 min to
a solution of (()-719,20 (1.06 g, 3.87 mmol) in dry Et2O (20 mL),
and the mixture was stirred at -20 °C under Ar. After 15
min, more cold Et2O (5 mL) was added to rinse down the flask
walls. After 1 h, the mixture was quenched with Et2O (30 mL)
and H2O and was stirred at room temperature for 30 min. The
mixture was then partitioned between Et2O (150 mL) and H2O
(50 mL), and the organic fraction was washed with brine before
it was dried (Na2SO4), filtered through Celite, and evaporated.
The crude product was purified by flash column eluting with
hexane/30% Et2O to yield 0.85 g of 8 (63%): 1H NMR (CDCl3)
δ 1.33 (t, J ) 7.0 Hz, 3H, CH3), 1.74-1.82 (m, 2H, H7 and
H4R), 1.86-1.91 (m, 1H, H6), 1.97-2.08 (m, 2H, H7 and H6),
2.35-2.40 (ddd, J ) 3.0, 13.0, 13.0 Hz, 1H, H4â), 3.20 (br s,
1H, OH), 3.61 (dd, J ) 12.5 and 5.5 Hz, 1H, H3R), 4.24 (q, J
) 7.0 Hz, 2H, OCH2), 4.27 (m, 1H, H1), 4.50 (br s, 1H, H5),
7.10 (tt, J ) 7.0 and 1.0 Hz, 1H, H4′′), 7.20 (m, 3H, H3′′, H5′′,
and H4′), 7.27 (t, J ) 8.0 Hz, 2H, H3′ and H5′), 7.39 (d, J )
8.0 Hz, 2H, H2′′ and H6′′), 7.53 (dd, J ) 8.0 and 1.0 Hz, 2H,
H2′ and H6′); 13C NMR (CDCl3) δ 14.7 (CH3), 24.8 (C7), 27.0
(C6), 36.9 (C4), 41.1 (C3), 53.6 (C5), 61.5 (OCH2), 65.5 (C1),
78.9 (C2, observed only when spectrum was recorded in a
mixture of CD3OD and CDCl3), 126.4 (C4′′), 126.9 (C2′ and
C6′), 127.0 (C4′), 127.89 and 127.92 (C3′, C5′ and C3′′, C5′′),
130.1 (C2′′, C6′′), 140.3 and 143.0 (C1′ and C1′), 156.1 (CO);
MS (EI) m/ z 351.20. Anal. (C22H25NO3) C, H, N.
(()-2r,3â-Dip h en yltr op a n -2-ol (3). With stirring at room
temperature under Ar, a solution of 8 (0.1129 g, 0.321 mmol)
in dry Et2O (3 × 1 mL) was added to a 1.0 M solution of LAH
in Et2O (0.96 mL, 0.96 mmol), and the mixture was heated to
reflux with stirring under N2. After 2 h, the mixture was
diluted with Et2O (8 mL) and quenched with a few drops of
saturated NaHCO3. The mixture was filtered through Celite,
and the filter cake was washed thoroughly with Et2O. The
combined filtrate was washed with saturated NaHCO3 and
brine before it was dried (Na2SO4), filtered through Celite, and
evaporated. The crude product was purified by radial PLC
on 1 mm silica gel plates eluting with CHCl3/2.5% MeOH/
0.25% NH4OH. The free base was converted to the HCl salt
with 1.0 M HCl in Et2O to yield 0.075 g of 3‚HCl (70%): mp
(()-2â,3â-Dip h en yltr op a n e (5). Compound 5 was pre-
pared from (()-10 (0.22 g, 0.65 mmol) and 1.0 M LAH in Et2O
(1.9 mL) using conditions similar to those for the preparation
of 4. The crude product was purified by radial PLC on 2 mm
silica gel plates eluting with CHCl3/2.5% MeOH/0.25% NH4-
OH. The product fractions were dried (Na2SO4), filtered
through Celite, and evaporated. Once concentrated, the
product solution was filtered through a cotton-plugged pipet
and evaporated to yield 0.16 g (90%) of (()-5, which was
converted to the HCl salt with 1.0 M HCl in Et2O: mp (HCl
1
(HCl salt) >250 °C dec; H NMR (CDCl3, free base) δ 1.65-
2.20 (complex, 6H, 3 CH2), 2.29 (s, 3H, NCH3), 2.89 (m, 1H,
CH), 3.16 (m, 1H, CH), 3.30 (dd, J ) 12.5 and 5.3 Hz, 1H,
CH), 5.44 (br s, 1H, OH), 6.90-7.20 (m, 6H, aromatic), 7.41
(d, J ) 7.0 Hz, 2H, aromatic), 7.49 (d, J ) 7 Hz, 2H, aromatic);
13C NMR (CDCl3, free base) δ 21.78, 24.87, 39.44, 40.47, 41.55,
61.26, 75.81, 76.29, 125.93, 126.53, 126.88, 127.77 (overlap of
two carbon peaks), 130.17, 141.88, 143.57; MS (EI) m/ z
293.25. Anal. (C20H23NO‚HCl‚0.75H2O) C, H, N.
1
salt) 140 °C dec; H NMR (free base, CDCl3) δ 1.65 (ddd, J )
13.0, 4.0, 4.0 Hz, 1H, H4R), 1.75-1.83 (m, 2H, H6 and H7),
2.13 (m, 1H, H6), 2.24 (s, 3H, NCH3), 2.28 (m, 1H, H7), 2.39
(ddd, J ) 13.0, 13.0, 2.6 Hz, 1H, H4â), 2.88 (dd, J ) 6.6, 2.4
Hz, 1H, H2), 3.31 (ddd, J ) 13.0, 6.6, 4.0 Hz, 1H, H3), 3.35
(m, 1H, H1), 3.40 (m, 1H, H5), 6.84-7.40 (complex, 10H,
aromatic); 13C NMR (free base, CDCl3) δ 25.0 (C6), 27.3 (C7),
35.2 (C4), 37.4 (C3), 42.0 (NCH3), 53.2 (C2), 61.9 (C5), 67.7
(C1), 125.4 (aromatic), 125.5 (aromatic), 127.0 (aromatic), 127.5
(aromatic), 128.0 (aromatic), 130.6 (aromatic), 142.8 (aromatic),
143.2 (aromatic). Anal. (C20H23N‚HCl‚0.5H2O) C, H, N.
(()-2r,3r-Dip h en yltr op a n e (6). Compound 6 was pre-
pared from (()-11 (0.093 g, 0.28 mmol) and 1.0 M LAH in Et2O
(0.83 mL) using conditions similar to those for the preparation
of 3. The crude product was purified by radial PLC on 1 mm
silica gel plates eluting with CHCl3/5% MeOH/0.5% NH4OH.
The product fractions were dried (Na2SO4), filtered through
Celite, and evaporated. Once concentrated, the product solu-
tion was filtered through a cotton-plugged pipet and evapo-
rated to yield 60.9 mg (79%) of (()-6, which was converted to
(()-8-(Eth oxyca r bon yl)-2,3-d ip h en yl-n or tr op -2-en e (9).
With stirring at 0 °C under N2, SOCl2 (0.79 mL, 10.8 mmol)
was added to a mixture of 8 (0.76 g, 2.17 mmol) and DBU (3.2
mL, 21.7 mmol) in dry CH2Cl2 (40 mL), and the mixture was
stirred at 0 °C under N2. After 1.5 h, more DBU (3.2 mL, 21.7
mmol) and SOCl2 (0.79 mL, 10.8 mmol) were added with
stirring at 0 °C under N2. After 1 h, the mixture was quenched
with H2O (10 mL) and was then partitioned between Et2O (500
mL) and H2O. The organic fraction was washed repeatedly
with H2O until the organic fraction was nearly colorless. The
organic fraction was then washed with brine before it was
dried (Na2SO4), filtered through Celite, and evaporated. The
crude product was purified by flash column, eluting with
hexane/10% Et2O to yield 0.63 g of 9 (87%): 1H NMR (CDCl3,
free base) δ 1.31 (br s, 3H, CH3), 1.82-3.10 (br m, 6H, 3 CH2),
4.21 (q, J ) 7.0 Hz, 2H, OCH2), 4.52 (br s, 1H, CH), 4.72 (br
s, 1H, CH), 6.90-7.20 (m, 10H, aromatic); 13C NMR (CDCl3,

2,3-Diphenyltropane Stereoisomers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8 1251
and serotonin transport sites in rat striatum and frontal cortex.
J . Med. Chem. 1994, 37, 1262-1268.
the HCl salt with 1.0 M HCl in Et2O: mp (HCl salt) 249-250
°C; 1H NMR (free base, CDCl3) δ 1.45 (m, 1H, H6), 1.79-1.94
(m, 2H, H7), 2.03 (m, 1H, H6), 2.09 (ddd, J ) 14.1, 6.2, 2.5
Hz, 1H, H4R), 2.35 (s, 3H, NCH3), 2.64 (ddd, J ) 14.1, 8.0, 8.0
Hz, 1H, H4â), 3.30 (m, 1H, H5), 3.55 (m, 1H, H1), 3.81 (ddd,
J ) 8.0, 8.0, 6.2 Hz, 1H, H3), 3.98 (dd, J ) 8.0, 5.0 Hz, 1H,
H2), 6.92-7.17 (complex, 10H, aromatic); 13C NMR (free base,
CDCl3) δ 22.57 (C7), 27.23 (C6), 36.87 (C3), 37.11 (C4), 40.70
(NCH3), 49.39 (C2), 60.45 (C5), 64.28 (C1), 124.8 (aromatic),
125.5 (aromatic), 127.2 (aromatic), 127.9 (aromatic), 128.3
(aromatic), 128.4 (aromatic), 142.7 (aromatic), 144.0 (aromatic).
Anal. (C20H23N‚HCl‚0.5H2O) C, H, N.
(13) Kotian, P.; Mascarella, S. W.; Abraham, P.; Lewin, A. H.; Boja,
J . W.; Kuhar, M. J .; Carroll, F. I. Synthesis, ligand binding, and
quantitative structure-activity relationship study of 3â-(4′-
substituted phenyl)-2â-(heterocyclic)tropanes: Evidence for an
electrostatic interaction at the 2â-position. J . Med. Chem. 1996,
39, 2753-2763.
(14) Carroll, F. I.; Gray, J . L.; Abraham, P.; Kuzemko, M. A.; Lewin,
A. H.; Boja, J .W.; Kuhar, M. J . 3-Aryl-2-(3′-substituted-1′,2′,4′-
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(15) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J . L.; Kuzemko,
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Kuhar, M. J . Cocaine and 3â-(4′-substituted phenyl)tropane-2â-
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(16) Kozikowski, A. P.; Saiah, M. K. E.; J ohnson, K. M.; Bergmann,
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Ack n ow led gm en t. This work was supported by the
National Institute on Drug Abuse (Grant No. DA05477).
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