Synthesis and ligand binding of tropane ring analogues of paroxetine

Article abstract of DOI:10.1021/jm970669p

(3S,4R)-4-(4-Fluoropheny)-3-[[3,4- (methylenedioxy)phenoxy]methyl]piperidine [(3S,9R)-3, paroxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans. In previous studies, we reported that certain (1R)-3β-(substituted

Full text of DOI:10.1021/jm970669p

J . Med. Chem. 1998, 41, 247-257
247
Syn th esis a n d Liga n d Bin d in g of Tr op a n e Rin g An a logu es of P a r oxetin e
Kathryn I. Keverline-Frantz,†,‡ J ohn W. Boja,§,| Michael J . Kuhar,§, Philip Abraham,† J ason P. Burgess,†
Anita H. Lewin,† 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 3, 1997
(3S,4R)-4-(4-Fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine [(3S,9R)-3, par-
oxetine] is a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant in humans.
In previous studies, we reported that certain (1R)-3â-(substituted phenyl)nortropane-2â-
carboxylic acid methyl esters (2a ) exhibited high affinity and reasonable selectivity for the
serotonin transporter (5-HTT). The major structural differences between 2a and (3S,4R)-3
are that 2a possesses a different absolute stereochemistry and has an ethylene bridge not
present in 3. In addition, 2a possesses a carbomethoxy substituent adjacent to the aryl ring,
whereas (3S,4R)-3 contains a [3,4-(methylenedioxy)phenoxy]methyl group. In this study, we
present the synthesis and biological evaluations of six of the possible eight isomers of 3-(4-
fluorophenyl)-2-[[3,4-(methylenedioxy)phenoxy]methyl]nortropane (4). The data for inhibition
of [3H]paroxetine binding show that (1R)-2â,3R-4c, which has the same stereochemistry as
paroxetine, has the highest affinity at the 5-HTT. Strikingly, the most potent compounds for
inhibition of [3H]WIN-35,428 binding were not the (1R)-2â,3â-isomers but rather (1R)-2â,3R-
4c and (1S)-2â,3R-4f. Conformational analyses show that these isomers exist in a flattened
boat conformation with pseudoequatorial substituents. Thus, the binding data show that this
conformation is recognized by the DAT-associated binding site and also suggest that this
conformation of paroxetine is recognized by the 5-HTT-associated binding site.
Much research has been devoted to gaining an un-
derstanding of the pharmacological action of cocaine
(1).1,2 Considerable evidence suggests that the reinforc-
ing or addicting properties of cocaine are due to its
ability to inhibit dopamine uptake in the limbic brain
area.3-7 Similar to dopamine, the reuptake of previ-
ously released serotonin plays the major role in regulat-
ing the synaptic availability of serotonin and thus
serotonergic neurotransmission. Numerous neurochem-
ical and behavioral outcomes are known to result from
the treatment of animals with serotonin uptake inhibi-
tors. For example, neuroendocrine, anticonvulsant, and
analgesic effects, as well as changes in food intake and
alcohol consumption, are observed.8 In addition, evi-
dence suggests that inhibition of serotonin reuptake
modulates the reinforcing properties of cocaine.9-13
Even though the importance of the serotonin trans-
porter in mediating the neurochemical and behavioral
actions of cocaine is now recognized, the molecular
mechanism of action and regulation of this transporter
are not well understood.
the serotonin transporter relative to the dopamine and
norepinephrine transporters. These compounds share
structural features with the 4-(4-fluorophenyl)-3-[[3,4-
(methylenedioxy)phenoxy]methyl]piperidine (3) class of
serotonin uptake inhibitors. The serotonin uptake
inhibitor paroxetine, which is (3S,4R)-3, has proven to
be an effective antidepressant in humans.8 Both classes
of compounds, 2 and 3, contain a piperidine ring with
an aryl moiety in a similar position. The major struc-
tural differences between 2a and (3S,4R)-3 are that (a)
in 2a the substituent â to the amino group is a
carbomethoxy group whereas the analogous position in
3 is occupied by a [3,4-(methylenedioxy)phenoxy]methyl
group, (b) the substituents in 2a are cis to each other
while they are in trans orientation in (3S,4R)-3, and (c)
in the nortropane 2a the positions R to the amino group
are ethylene bridged. To gain a better understanding
of the important structural features required by the
nortropane class of compounds for good affinity and
selectivity at serotonin transporters, we have prepared
and evaluated the transporter binding properties of six
of the possible eight isomers of 3-(4-fluorophenyl)-2-
[[3,4-(methylenedioxy)phenoxy]methyl]nortropane (4).
We, and others, have reported that certain (1R)-3â-
(substituted phenyl)nortropanes possessing 2â-carbox-
ylic acid ester groups (2a )14 and 2â-ketone groups (2b)15
exhibit high potency at, and reasonable selectivity for,
Syn th esis
† Research Triangle Institute.
Scheme 1 outlines the general synthesis used to
prepare the nortropane analogues 4. Lithium alumi-
num hydride reduction of the appropriate 3-(4-fluoro-
phenyl)tropane-2-carboxylic acid methyl ester isomer 5
gives the 2-(hydroxymethyl)tropane 6. Treatment of 6
with methanesulfonyl chloride afforded the 2-hydroxy-
methyl mesylate which, when heated in a tetrahydro-
‡ Current address: Department of Chemistry, Delaware Valley
College, 700 East Butler Ave, Doylestown, PA 18901.
§ NIDA.
| Current address: Department of Pharmacology, Northeastern Ohio
University, College of Medicine, 4209 State Route 44, Rootstown, OH
44272.
Current address: Yerkes Regional Primate Research Center,
Emory University, 954 Gatewood NE, Atlanta, GA 30329.
S0022-2623(97)00669-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/15/1998

248 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Keverline-Frantz
Sch em e 1
corresponding (1R) analogues.18 The addition of N-
phenyltrifluoromethanesulfonimide to a tetrahydro-
furan solution of (1S)-2-carbomethoxy-3-tropinone (11)19
containing sodium bis(trimethylsilyl)amide yielded tri-
flate 12. This triflate was utilized in two ways. Treat-
ment of 12 with triethylamine, formic acid, triphenyl-
phosphine, and palladium catalyst gave (1S)-anhydro-
ecgonine methyl ester (13).18 The (1S)-3â-(4-fluoro-
phenyl)tropane-2â-carboxylic acid methyl ester [(1S)-
2â,3â-5] was synthesized as described previously for
(1R)-2â,3â-5.16 Treatment of (1S)-2â,3â-5 with sodium
methoxide in methanol afforded (1S)-2R,3â-5. Reaction
of 12 with (4-fluorophenyl)boronic acid in refluxing
diethoxymethane using tris(dibenzilideneacetone)di-
palladium(0) as catalyst, followed by chromatographic
purification, gave the (4-fluorophenyl)tropene 14.18 Re-
duction of 14 with samarium (II) iodide at -78 °C using
methanol as the proton source, followed by quenching
with trifluoroacetic acid at 0 °C, gave a mixture of (1S)-
3R-(4-fluorophenyl)-2â-carboxylic acid methyl ester [(1S)-
2â,3R-5] as the major product and (1S)-3â-(4-fluoro-
phenyl)-2â-carboxylic acid methyl ester [(1S)-2â,3â-5],
which were separated by column chromatography.
furan:DMF (5:1) mixture containing 18-crown-6 with the
sodium salt of sesamol, yields 3-(4-fluorophenyl)-2-[[3,4-
(methylenedioxy)phenoxy]methyl]tropane 7. N-Demeth-
ylation using 1-chloroethyl chloroformate (ACE-Cl) in
ethylene dichloride followed by treatment with metha-
nol, or using trichloroethyl chloroformate followed by
treatment with zinc, affords the nortropane analogues
4.
The synthesis used to prepare three of the 3-(4-
fluorophenyl)tropane-2-carboxylic acid methyl esters (5)
(possessing the (1R)-configuration) is shown in Scheme
2. The addition of (p-fluorophenyl)magnesium bromide
to anhydroecgonine methyl ester (8), which was derived
from (-)-cocaine as previously reported, gives (1R)-
2â,3â-5.16 Isomerization of (1R)-2â,3â-5 with sodium
methoxide in methanol affords (1R)-2R,3â-5. The ad-
dition of (p-fluorophenyl)lithium to the R,â-unsaturated
1,2,4-oxadiazole 9 gives the cis-addition product 10.
Subjection of 10 to reduction with nickel boride in
methanol results in conversion of the oxadiazole to a
methyl ester and effects complete isomerization at the
2-position to give (1R)-2â,3R-5.17 We had hoped to
prepare (1R)-2R,3R-5 by appropriate modification of this
reductive opening of the oxadiazole ring to the 2â-
methyl ester. However, all attempts to effect this
conversion resulted in isomerization of the 2R group to
the 2â-isomer.
Specific structural and stereochemical assignments
were made for the compounds (1R)-7 and (1R)-4 using
1
1D H and 13C NMR spectra and 2D COSY,20,21 NOE-
SY,22 and HQMC23 spectra. Thus, the presence of a
1
large (10.6 Hz) coupling in the pattern of H3 in the H
NMR spectrum of (1R)-2â,3â-7a requires H3 to be axial,
showing that the aryl substituent at C3 must occupy
the equatorial (â) position. Similarly, the magnitude
of J 2,3 (5.8 Hz), which is characteristic of axial-equato-
rial coupling, taken together with the axial nature of
H3, mandates that H2 must be equatorial, confirming
the â-position of the C2 substituent. The observed
NOESY interaction between H3 and H6 further con-
firms the axial configuration of H3 and requires that
(1R)-2â,3â-7a be in the chair conformation. Similar
arguments confirm the structural assignment of 2â,3â-
4a . The observation of two large coupling constants (J
) 12.0 Hz) for H3, which are both (COSY) associated
with H2 and H4â, characterize the structure of 2R,3â-
7b. The observed NOESY interactions of H2 with H4â
and of H3 with H6 provide further evidence for the
2R,3â-sterochemistry and show that the compound is
Three of the (1S) isomers of 3-(4-fluorophenyl)tropane-
2-carboxylic acid methyl esters were prepared by routes
given in Scheme 3. The synthesis of 12-14, (1S)-2â,3R-
5, and (1S)-2â,3â-5 is analogous to that presented in a
preliminary communication for the synthesis of the

Tropane Ring Analogues of Paroxetine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 249
Sch em e 2
Sch em e 3
in the chair conformation. The structure of the N-nor
analogue 2R,3â-4b is deduced from similar consider-
ations. The compound 2â,3R-7c also exhibits two large
couplings and one smaller coupling for H3. The large
couplings (J ) 10.8 and 10.3 Hz) are associated with
H2 and H4R, respectively, while the smaller coupling
(J ) 8.3 Hz) is associated with H4â. In addition, the
NOESY spectrum shows an interaction between H2 and
H4R. These observations cannot be reconciled with a
chair conformation for this compound. Since the struc-
tures of the 3â isomers are definite, this isomer must
possess a 3R substituent, i.e., H3 must be equatorial.
However, the two large coupling constants between H3
and its geminal neighbors are inconsistent with dihedral
angles of ∼60°, which are associated with equatorial-
equatorial or equatorial-axial protons in a chair con-
formation. Therefore, the preferred conformation for
this compound must be boatlike. This observation is
supported by molecular modeling where the global
energy minimum conformation was found to be a

250 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Keverline-Frantz
Ta ble 1. Comparison of Transporter Binding Potencies of the Isomers of 4 and 7
IC50 (nM)a
stereochemistry
5-HT
DA
NE
DA/5-HT
ratiob
NE/5-HT
ratiob
compd
R
2
3
[3H]Paroxetine
[3H]WIN 35,428
[3H]Nisoxetine
paroxetine
(1R)-7a
(1R)-4a
(1R)-7b
(1R)-4b
(1R)-7c
(1R)-4c
(1S)-7d
(1S)-4d
(1S)-7e
(1S)-4e
(1S)-7f
(1S)-4f
0.28 ( 0.02
294 ( 18
480 ( 21
52.9 ( 3.6
90 ( 3.4
422 ( 16
5.62 ( 0.2
88.1 ( 2.8
424 ( 15
447 ( 47
55.8 ( 5.73
178 ( 13
19 ( 1.8
623 ( 25
308 ( 20
835 ( 90
172 ( 8.8
142 ( 13
3.01 ( 0.2
3.86 ( 0.2
1050 ( 45
1210 ( 33
1500 ( 74
27.6 ( 2.4
298 ( 17
407 ( 33
535 ( 15
2230
1910
18
78
500
28
0.29
2.6
310
41
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
â
â
5300 ( 450
37400 ( 1400
26600 ( 1200
2500 ( 250
123 ( 9.5
1.0
1.7
3.3
1.6
0.007
0.7
12
2.9
32
0.49
1.7
21
â
R
R
â
â
â
â
R
R
â
â
â
â
â
R
R
â
â
â
â
R
R
14.4 ( 1.3
27600 ( 1100
17300 ( 1800
2,916 ( 1950
1690 ( 150
12400 ( 720
1990 ( 176
640
30
70
100
a
b
Data are mean ( standard error of three or four experiments with triplicate values at each concentration. DA/5-HT and NE/5-HT
are ratios of IC50 values.
flattened boat. This conformation is preferred over the
lowest energy chair conformation by >3 kcal/mol. The
similarity of the NMR parameters of the N-nor analogue
2â,3R-4 indicates that it exists in a similar conforma-
tion.
cocaine is now recognized, the biochemical mechanism
of action and regulation of this transporter is not well
understood.
The nortropane derivatives 4 were designed to be
similar to known serotonin uptake inhibitors 3. Both
classes of compounds contain a piperidine ring with a
4-fluorophenyl group and a [3,4-(methylenedioxy)phe-
noxy]methyl moiety in similar positions on the ring. The
eight possible isomers of 4 are listed in Figure 1. The
major structural difference between 3 and 4 is the
presence of an ethylene bridge, not present in 3, which
leads to reduced conformational heterogeneity. For
example, whereas the piperidine ring in the (3S,4R)-
isomer of 3, which is paroxetine, may interconvert
between the chair conformations Caa and Cee, and the
boat conformation Bee and Baa, the piperidine ring in
the analogous isomer of 4 can only interconvert between
the chair and boat conformations (see Figure 2) but not
between two chair conformations. In the series of
analogues 3, the potency of paroxetine, i.e., the trans-
(+)-3S,4R isomer, exceeds that of the other isomers by
factors of 60-160.36 This isomer may exist in either a
diequatorial (Cee) or a diaxial (Caa) chair conformation,
as well as in boat conformations Baa and Bee, all of which
are interconvertible. The chair conformations Caa and
Cee are mimicked by the isomers (1R)-2â,3R-4c and (1S)-
2R,3â-4e, respectively, each of which can adopt a boat
conformation, but which are not interconvertible. There-
fore, it would be expected that, if conformation Cee were
responsible for the high potency of paroxetine, (1S)-
2R,3â-4e would possess high potency to inhibit [3H]-
paroxetine binding. Conversely, if conformation Caa
were the potent form of paroxetine, (1R)-2â,3R-4c would
exhibit high potency. However, since the chair confor-
mation of (1R)-2â,3R-4c possesses two axial substitu-
ents, the chair may not be the energy minimum con-
formation for this compound. Thus, we had found that
although the chair is the preferred conformation of
allococaine, the (2R,3R)-diaxial isomer of cocaine, boat
Liga n d Bin d in g Stu d ies
IC50 values at the DA, NE, and 5HT transporters
represent inhibition of 0.5 nM [3H]WIN 35,428, 0.5 nM
[3H]nisoxetine, and 0.2 nM [3H]paroxetine binding,
respectively, and were determined as previously de-
scribed.24 The IC50 values for paroxetine, the six
nortropane analogues 4, and six N-methyl analogues 7
are listed in Table 1.
Discu ssion
Cocaine (1) is an inhibitor of the neuronal transport
of norepinephrine (NE), dopamine (DA), and serotonin
(5-HT) at roughly similar concentrations, i.e., with Ki’s
between 220 and 310 nM.25 Biochemical binding stud-
ies indicate slight DA selectivity.26,27 In recent years,
structure-activity relationship studies of cocaine ana-
logues for binding at monoamine transporters, particu-
larly at the dopamine transporter, have been
explored,26-32 and some structural modifications that
result in selectivity for the dopamine transporter over
the norepinephrine and serotonin transporters have
been reported.33-35 In the introduction section, we
pointed out that serotonergic activity may affect the
reinforcing effects of cocaine. Since the in vitro potency
of cocaine (1) to inhibit serotonin reuptake is essentially
identical with its potency to inhibit dopamine reuptake,
some of the pharmacological properties of cocaine might
be due to its inhibition of reuptake of serotonin. Even
though the importance of the serotonin transporter in
mediating the neurochemical and behavioral actions of

Tropane Ring Analogues of Paroxetine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 251
F igu r e 1. Isomers of 4.
conformations were preferred for diaxial analogues of
3-aryltropane-2-carboxylates.17,37
to note that both (1R)-2â,3â-4a and (1S)-2â,3â-4d had
low affinity for all three transporters. The low affinity
of (1R)-2â,3â-7a and its N-nor analogue (1R)-2â,3â-4a
at the DAT relative to the (1R)-2â,3R-isomers is par-
ticularly striking. Thus, since the ratio of potencies to
inhibit radioligand binding at the DAT for cocaine,
which has the (1R)-2â,3â configuration, to allococaine,
which has (1R)-2â,3R configuration, is 59,40 it might
have been expected that the potency of the (1R)-2â,3â-
7a and (1R)-2â,3â-4a would exceed that of their (1R)-
2â,3R-isomers. Instead, the ratio is 0.01 for (1R)-2â,3â-
7a to (1R)-2â,3R-7c and 0.005 for (1R)-2â,3â-4a to (1R)-
2â,3R-4c. This unexpected result may be attributable
to the flattened boat conformation of (1R)-2â,3R-7c and
(1R)-2â,3R-4c. A less striking but similar situation had
been observed for the isomeric 3-phenyl-2-(3-methyl-
1,2,4-oxadiazol-5-yl)tropanes, where the potency of the
2â,3R isomer, which exists in a boat conformation, was
only slightly lower (1.48) than that of the 2â,3â isomer,
which exists in a chair conformation.37
Binding affinities at the 5-HT transporter, determined
by inhibition of [3H]paroxetine binding (Table 1), show
that the diequatorial isomers, (1R)-2R,3â-4b and (1S)-
2R,3â-4e, are substantially less potent than the diaxial
isomers, (1R)-2â,3R-4c and (1S)-2â,3R-4f, demonstrating
that conformation Cee, which may well be the low-energy
conformation of paroxetine, is not well accommodated
by the receptor at the 5-HT transporter. The most
potent of the isomers is (1R)-2â,3R-4c, suggesting that
its conformation best mimics the conformation of par-
oxetine which is recognized by the receptor. Since the
preferred conformation of the piperidine ring of (1R)-
2â,3R-4c is a substantially flattened boat, it appears
that a relatively flat conformation may be required for
paroxetine to bind the receptor at the 5-HT transporter.
Such a conformation could resemble both the (1R)- and
the (1S)-isomers of 2â,3R-4c, and indeed, the potency
of (1R)-2â,3R-4c is only 3.4 times greater than that of
the (1S)-isomer. The more than 1 order of magnitude
lower potency of (1R)-2â,3R-4c (IC50 ) 5.62 nM) relative
to paroxetine (IC50 ) 0.28 nM) may be due to steric
inhibition of binding by the ethylene bridge in (1R)-
2â,3R-4c.
The fact that several 3â-(para-substituted phenyl)-
tropane-2â-carboxylic acid methyl esters, which possess
the natural (1R)-cocaine stereochemistry, have high
afffinity at the 5-HT site38 suggested that (1R)-2â,3â-
4a (i.e., an analogue of the cis isomer of paroxetine)
might also possesss high affinity at the 5-HT trans-
porter. Additionally, it had been shown that N-de-
methylation of 3â-(p-fluorophenyl)-2â-carbomethoxy-
tropane (WIN 35,428) to give the N-nor analogue (RTI-
142) resulted in increased affinity at the DA, 5-HT, and
NE transporters.39 The data in the Table indicate that
these observations do not generalize to this set of
compounds. In other words, N-demethylation leads to
increased potency at 5-HT transporters only for the
isomers which preferentially exist in a boat conforma-
tion; the effect on potency at DA and NE transporters
appears to be random. In addition, it was surprising
Con clu sion s
Six of the possible eight stereoisomers of 3-(4-fluoro-
ph en yl)-2-[[3,4-(m et h ylen edioxy)ph en oxy]m et h yl]-
nortropane (4) have been prepared as analogues of
paroxetine. Ligand binding data show that (1R)-2â,3R-
4c, which is one of the isomers that has the same
relative stereochemistry as paroxetine, has the highest
affinity for the 5-HT transporter. Since this isomer
exists in a flattened boat conformation with pseudo-
equatorial substituents, it appears that a flattened boat
conformation of paroxetine is recognized by the binding
site at the 5-HT transporter. The order of magnitude
lower potency of (1S)-2R,3â-4e, which is the other isomer
that has the same relative stereochemistry as parox-
etine, confirms that a chair conformation with two
equatorial substituents is not recognized by the 5-HT
transporter-associated receptor. The good affinity of
(1R)-2â,3R-4c and (1R)-2â,3R-7c at the DA transporter
suggests that tropane analogues which exist in a flat-

252 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Keverline-Frantz
F igu r e 2. Chair and boat conformations.
AMX-500 spectrometer operating at 500.13 MHz for 1H using
a Bruker 5 mm inverse detect broadband probe. The double
quantum filtered phase sensitive COSY20,21 and NOESY22 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. NOESY spectra were ob-
tained with a 1200 ms mixing time and a recycle delay of 4 s.
Heteronuclear multiple quantum correlation (HMQC)23 spectra
were acquired as 1024 × 256 data points with a spectral width
of 4800 Hz in F2 and 24 375 Hz in F1. An average coupling
constant of 145 Hz was used to optimize 1/2J CH delays. The
data were apodized with a squared sine function and zero filled
to 2048 × 512 data points prior to Fourier transformation.
tened boat conformation with pseudoequatorial substit-
uents are well recognized by the DAT-associated binding
site.
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capil-
lary tube apparatus. All optical rotations were determined
at the sodium D line using a Rudolph Research Autopol III
polarimeter (1 dm cell). Thin-layer chromatography was
carried out on Whatman silica gel 60 TLC plates, and flash
chromatography was conducted on silica gel 60 (230-400
mesh). Visualization was accomplished under UV or in an
iodine chamber. Microanalyses were carried out by Atlantic
Microlab, Inc. Tropinone was purchased from Lancaster
Synthesis, Inc., and samarium iodide was from Fluka Chemi-
cal Corp. All other chemicals were purchased from Aldrich
Chemical Co, Inc. THF and ether were freshly distilled from
sodium benzophenone. All other reagents were used without
further purification.
Molecu la r Mod elin g Stu d ies. Molecular modeling was
performed on a SGI O2 using Sybyl 6.341 and Spartan.42
Minimum energy structures were obtained using the simulated
annealing module in Sybyl. For each structure, 50 cycles were
calculated with a simulated temperature of 500 K for 500 fs
and then annealed to 200 K for 500 fs with an exponential
ramping function. The overall boat or chair conformation was
maintained during the annealing procedure by placing a
Nu clea r Ma gn etic Reson a n ce Stu d ies. Routine NMR
spectra were obtained on a Bruker AM-250 spectrometer.
COSY, NOESY, and HMQC spectra were recorded on a Bruker

Tropane Ring Analogues of Paroxetine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 253
penalty function on the N-C3 torsional angle with an equi-
librium value of 0° for the boat conformation and 65° for the
chair conformation. The lowest energy structures for each
conformation were transferred to Spartan where the structures
were further optimized using MM3; then the heats of forma-
tion were obtained from semiempirical (AM1) quantum me-
chanics calculations.
gave 0.540 g (72%) of white solid: mp 83-85 °C; 1H NMR
(CDCl3) δ 1.49 (m, 2H), 1.74 (m, 2H), 2.05 (m, 2H), 2.23 (s,
3H), 2.47 (m, 1H), 2.94 (m, 2 H), 3.23 (m, 2H), 3.65 (m, 1H),
3.85 (m, 1H), 6.96 (m, 2H), 7.25 (m, 2H); 13C NMR (CDCl3) δ
160.99 (d), 141.98, 128.63, 128.57, 114.93, 114.77, 68.69, 64.94,
60.16, 49.88, 40.83, 38.01, 35.49, 27.07, 26.62; [R]D +38.6° (c
0.29, CHCl3). Anal. (C15H20FNO‚0.5H2O) C, H, N.
Gen er a l Syn th esis of 3-(4-F lu or op h en yl)-2-(h yd r oxy-
m eth yl)tr op a n e (6). A solution of 5 (3.0 mmol) in 10 mL of
Et2O was added dropwise to a cooled slurry (0 °C) of lithium
aluminum hydride (5.0 mmol) in 20 mL of anhydrous Et2O.
The reaction mixture was stirred at room temperature for 2 h
and then cooled to 0 °C and quenched with NH4Cl (∼3 mL).
Water was added, and the layers were separated. The aqueous
layer was extracted with Et2O. The organic layers were
combined, and the solvent was removed to afford a white solid
which was recrystallized from hexanes or EtOAc. Results from
each isomer are described in the following experiments.
(1R )-3â-(4-F lu o r o p h e n y l)-2â-(h y d r o x y m e t h y l)t r o -
p a n e [(1R)-2â,3â-6]. Recrystallization from hexanes gave
P r oced u r e for th e Gen er a l Syn th esis of 3-(4-F lu or o-
p h e n y l)-2-[[3,4-(m e t h y le n e d io x y )p h e n o x y ]m e t h y l]-
tr op a n e (7). A solution of the appropriate isomer of 6 (2.0
mmol) in 15 mL of CH2Cl2 was cooled to 0 °C, and methane-
sulfonyl chloride (2.5 mmol) was added. Et3N (2.0 mmol) was
then added dropwise. The reaction mixture was stirred at 0
°C for 0.5 h and then at room temperature. After 3 h, CH2Cl2
and water were added. The reaction was basified to pH 10
with NH4OH, and the layers were separated. The aqueous
layer was extracted with CH2Cl2. The organic layers were
combined, washed with 1 N NaOH, water, NH4Cl solution,
water, and NaCl solution, and dried over Na2SO4. The solvent
was removed to give a colorless, slightly cloudy oil which was
used without further purification.
0.745 g (83%) of white solid: mp 75-78 °C; [R]25 -59.8° (c
D
1
0.5, CHCl3); H NMR (CDCl3) δ 1.46 (m, 1H), 1.58-1.67 (m,
Sodium hydride (60% dispersion, 4.0 mmol) was washed
twice with hexanes under nitrogen gas. Anhydrous THF (10
mL) was added, and the slurry was cooled to 0 °C. A solution
of sesamol (4.0 mmol) in 10 mL of THF was added dropwise.
Eventually the mixture cleared and became yellow. The
alkoxide was warmed to room temperature and refluxed for
45 min. The mesylate and 18-crown-6 ether (∼5 mg) were
dissolved in 10 mL of a mixture of THF and 2 mL of DMF and
added dropwise over 10 min. The reaction was warmed to
room temperature after the addition was complete, refluxed
for 3 h, and then stirred at room temperature for 2 h. The
reaction mixture was cooled to 0 °C and quenched with water.
THF was removed under reduced pressure, water and NH4OH
were added, and the aqueous layer (pH 10) was extracted with
CH2Cl2. The organic layers were combined, washed with 1 N
NaOH, water, and NaCl solution, and dried over MgSO4. The
solvent was removed to give a light yellow oil which was
purified by flash chromatography on silica gel, eluting with
Et2O/Et3N/hexanes (27:3:70).
1H), 1.72 (s, 1H), 1.75 (s, 1H), 2.16 (m, 2H), 2.28 (s, 3H), 2.50
(m, 1H), 3.07 (m, 1H), 3.35 (m, 2H), 3.46 (m, 1H), 3.75 (m,
1H), 7.01 (m, 2H), 7.32 (m, 2H). Anal. (C15H20FNO) C, H, N.
(1R )-3â-(4-F lu o r o p h e n y l)-2r-(h y d r o x y m e t h y l)t r o -
p a n e [(1R)-2r,3â-6]. Recrystallization from EtOAc gave
0.494 g (79%) of white solid: mp 174-176 °C; [R]D +26.3° (c
0.62, CHCl3); 1H NMR (CDCl3) δ 1.54-1.62 (m, 2H), 1.70-
2.22 (m, 6H), 2.27-2.35 (m, 1H), 2.35 (s, 3H), 3.20-3.41 (m,
4H), 6.96 (m, 2H), 7.18 (m, 2H); 13C NMR (CDCl3) δ 162.33
(d), 139.21, 128.77, 128.64, 115.08, 114.74, 62.41, 61.43, 48.58,
40.84, 40.59, 37.19, 25.48, 21.26. Anal. (C15H20FNO) C, H,
N. The alcohol was converted to the D-tartrate salt. Recrys-
tallization from MeOH/Et2O gave a white hygroscopic pow-
der: mp 89 °C (fusion); 1H NMR (CD3OD) δ 1.88-2.39 (m, 7H),
2.72 (m, 1H), 2.87 (s, 3H), 3.25 (dd, 2H), 3.96 (m, 1H), 4.07
(m, 1H), 7.05 (m, 2H), 7.31 (m, 2H); [R]25 +3.5° (c 0.20,
D
CH3OH). Anal. (C19H26FNO7) C, H, N.
(1R )-3r-(4-F lu o r o p h e n y l)-2â-(h y d r o x y m e t h y l)t r o -
p a n e [(1R)-2â,3r-6]. Recrystallization from hexanes gave
0.681 g (64%, two steps from oxadiazole 10) of white solid: mp
83-84 °C; 1H NMR (CDCl3) δ 1.43-1.56 (m, 2H), 1.74 (m, 1H),
1.84 (m, 1H), 2.01-2.13 (m, 2H), 2.23 (s, 3H), 2.46 (m, 1H),
2.95 (m, 1 H), 3.24 (m, 2H), 3.64 (m, 1H), 3.83 (m, 1H), 6.96
(m, 2H), 7.24 (m, 2H); 13C NMR δ (CDCl3) 163.27 (d), 142.79,
128.66, 128.54, 115.09, 114.75, 69.11, 65.21, 60.27, 49.62,
40.88, 37.82, 35.53, 26.95, 26.53; [R]D -41.9° (c 0.31, CHCl3).
Anal. (C15H20FNO) C, H, N. The product was converted to
the D-tartrate salt. Recrystallization from (CH3)2CHOH/Et2O
gave a hygroscopic off-white solid: mp 79 °C (fusion); 1H NMR
(CD3OD) δ 1.86 (m, 1H), 2.02-2.13 (m, 3H), 2.30-2.72 (m, 3H),
2.78 (s, 3H), 3.01 (m, 1H), 3.51 (m, 2H), 3.88 (m, 1H), 7.06 (m,
(1R)-3â-(4-F lu or op h en yl)-2â-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]tr op a n e [(1R)-2â,3â-7a ]. Purification by
flash chromatography gave 0.33 g (44%) of the pure product
as an oil: 1H NMR (C6D6) δ 1.59 (m, 1H), 1.81 (m, 2H), 2.09
(m, 2H), 2.14 (m, 1H), 2.20 (ddd, 1H, J ) 14.3, 5.8, 5.8 Hz),
2.38 (ddd, 1H, J ) 11.6, 1.6, 1.6 Hz), 2.40 (s, 3H), 2.98 (dd,
1H, J ) 11.6, 6.2 Hz), 3.01 (ddd, 1H, J ) 6.2, 6.2, 1.6 Hz),
3.42 (dd, 1H, J ) 10.6, 5.8 Hz), 4.31 (ddd, 1H, J ) 9.7, 1.8, 1.8
Hz), 5.89 (s, 2H), 6.32 (dd, 1H, J ) 8.6, 2.3 Hz), 6.48 (d, 1H, J
) 2.3 Hz), 6.66 (d, 1H, J ) 8.6 Hz), 6.95 (dd, 2H, J ) 8.8, 8.8
Hz), 7.39 (dd, 2H, J ) 8.8, 5.8 Hz); 13C NMR (CDCl3) δ 163.06,
159.20, 152.75, 148.28, 143.23, 141.82, 129.45, 129.33, 115.12,
114.78, 108.57, 108.09, 101.15, 99.90, 83.74, 55.25, 50.49,
54.52, 42.89, 33.96, 31.96, 26.98, 23.38. The D-tartrate salt
recrystallized from 2-propanol/ethyl ether yielded a white
powder which had mp 97 °C (fusion): 1H NMR (CD3OD) δ
2.00-2.43 (m, 7H), 2.95 (s, 3H), 3.48 (m, 2H), 3.68 (m, 2H),
4.61 (m, 1H), 5.86 (s, 2H), 6.39 (dd, 1H), 6.49 (d, 1H), 6.68
2H), 7.35 (m, 2H); [R]25 -24.0° (c 0.48, CH3OH). Anal.
D
(C19H26FNO7‚0.5 H2O) C, H, N.
(1S )-3â-(4-F lu o r o p h e n y l)-2â-(h y d r o x y m e t h y l)t r o -
p a n e [(1S)-2â,3â-6]. Recrystallization from hexanes gave 1.18
g (70%) of white solid: mp 77-79 °C; 1H NMR (CDCl3) δ 1.46
(m, 1H), 1.67-1.58 (m, 1H), 1.72 (s, 1H), 1.75 (s, 1H), 2.16 (m,
2H), 2.28 (s, 3H), 2.50 (m, 1H), 3.07 (m, 2H), 3.35 (m, 2H),
3.46 (m, 1H), 3.75 (m, 1H), 7.01 (m, 2H), 7.32 (m, 2H); 13C NMR
(CDCl3) δ 161.42, 138.41, 129.86, 129.73, 115.13, 114.80, 68.56,
65.21, 61.96, 45.49, 41.19, 37.32, 36.19, 26.29, 25.18. [R]D
+58.9° (c 0.54, CHCl3). Anal. (C15H20FNO) C, H, N.
(1S )-3â-(4-F lu o r o p h e n y l)-2r-(h y d r o x y m e t h y l)t r o -
p a n e [(1S)-2r,3â-6]. Recrystallization from EtOAc gave 0.88
(dd, 1H), 7.03 (m, 2H), 7.36 (m, 2H); [R]25 +11.8° (c 0.27,
D
CH3OH). Anal. (C26H30FNO9) C, H, N.
3â-(4-F lu o r o p h e n y l)-2r-[[3,4-(m e t h y le n e d i o x y )-
p h en oxy]m eth yl]tr op a n e [(1R)-2r,3â-7b]. Fractions were
pooled to give 0.34 g (51%) of the product as a colorless oil:
1H NMR (C6D6) δ 1.37 (ddd, 1H, J ) 12.0, 9.6, 4.8 Hz), 1.44
(ddd, 1H, J ) 12.0, 5.7, 3.0 Hz), 1.71 (m, 1H), 1.77 (m, 1H),
1.87 (ddd, 1H, J ) 12.0, 6.4, 6.4 Hz), 1.94 (ddd, 1H, J ) 12.0,
12.0, 3.4 Hz), 2.20 (s, 3H), 2.31(ddd, 1H, J ) 12.0, 12.0, 5.7
Hz), 2.65 (ddd, 1H, J ) 12.0, 9.6, 3.5 Hz), 3.00 (dd, 1H, J )
6.4, 6.4, 3.0 Hz), 3.40 (dd, 1H, J ) 9.6, 9.6 Hz), 3.49 (dd, 1H,
J ) 9.6, 3.5 Hz), 3.52 (dd, 1H, J ) 6.7, 3.0 Hz), 5.33 (s, 2H),
6.12 (dd, 1H, J ) 8.5, 2.5 Hz), 6.49 (d, 1H, J ) 2.5 Hz), 6.56
(d, 1H, J ) 8.5 Hz), 6.79 (dd, 2H, J ) 8.7, 8.7 Hz), 6.94 (dd,
2H, J ) 8.7, 5.5 Hz); 13C NMR (CDCl3) δ 154.45, 148.30,
144.66, 139.53, 129.33, 129.20, 115.73, 115.40, 107.98, 105.68,
1
g (66%) of white solid: mp 173-175 °C; H NMR (CDCl3) δ
1.54-1.62 (m, 2H), 1.70-2.22 (m, 6H), 2.27-2.35 (m, 1H), 2.36
(s, 3H), 3.20-3.41 (m, 4H), 6.96 (m, 2H), 7.18 (m, 2H); 13C NMR
(CDCl3) δ 161.42 (d), 139.69, 129.22, 129.09, 115.44, 115.11,
62.71, 62.15, 61.90, 49.28, 41.20, 41.00, 37.53, 25.84, 21.62;
[R]D -24.7° (c 0.51, CHCl3). Anal. (C15H20FNO) C, H, N.
(1S )-3r-(4-F lu o r o p h e n y l)-2â-(h y d r o x y m e t h y l)t r o -
p a n e [(1S)-2â,3r-6]. Recrystallization from Et2O/hexanes

254 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Keverline-Frantz
101.23, 98.14, 70.84, 68.91, 63.28, 62.01, 46.23, 41.55, 41.23,
37.54, 26.10, 22.07. The compound was converted to the
D-tartrate salt. Recrystallization from EtOH/Et2O gave a
hygroscopic off-white powder: mp 105 °C (fusion); 1H NMR
(CD3OD) δ 1.95 (m, 1H), 2.13-2.46 (m, 5H), 2.77-3.00 (m, 2H),
2.89 (s, 3H), 3.46-3.70 (m, 2H) 3.99 (m, 1H), 4.14 (m, 1H),
4.43 (s, 2H), 5.84 (s, 2H), 6.15 (dd, 1H), 6.35 (d, 1H), 6.62 (d,
1H), 7.06 (m, 2H), 7.35 (m, 2H); [R]25D +32.8° (c 0.29, CH3OH).
Anal. (C26H30FNO9) C, H, N.
Meth od B. The appropriate isomer of 7 (1.0 mmol) was
dissolved in 10 mL of toluene under nitrogen gas. Potassium
carbonate (0.4 mmol) was added, and the solution was refluxed
for 0.5 h. Trichloroethyl chloroformate (3.8 mmol) was added,
and the reaction was refluxed for 24 h. Additional chloro-
formate was added, and the reaction was refluxed for 24 h.
Water and CHCl3 were added, and the reaction mixture was
basified with NH4OH. The layers were separated, and the
aqueous layer was extracted with CHCl3. The combined
organic layers were dried over Na2SO4. The solvent was
removed to afford a brown oil. The carbamate was dissolved
in glacial acetic acid (6.0 mL), and Zn dust (1.00 g) was added
in small portions. The mixture was stirred for 12 h at room
temperature. Water and CHCl3 were added, and the reaction
was filtered through Celite. After basifying with NH4OH and
extracting with CHCl3, the organic layers were dried over
K2CO3. The product was purified by flash chromatography
on silica gel, first eluting with Et2O/Et3N (9:1) followed by
CHCl3/CH3OH/NH4OH (90:9:1).
3r-(4-F lu or op h en yl)-2â-[[(3,4-(m et h ylen ed ioxy)p h e-
n oxy]m eth yl]tr opan e [(1R)-2â,3r-7c]. Fractions were pooled
to give 0.312 g (42%) of the product as a light yellow oil: 1H
NMR (C6D6) δ 1.25 (dd, 1H, J ) 13.2, 10.8 Hz), 1.50 (ddd, 1H,
J ) 12.5, 9.5, 3.4 Hz), 1.59 (ddd, 1H, J ) 17.0, 12.1, 4.9 Hz),
1.87 (ddd, 1H, J ) 10.8, 10.8, 3.5 Hz), 2.13 (ddd, 1H, J ) 17.0,
12.1, 5.8 Hz), 2.29 (m, 4H), 2.46 (ddd, 1H, J ) 13.2, 8.6, 8.3
Hz), 2.62 (ddd, 1H, J ) 10.8, 10.3, 8.3 Hz), 3.29 (m, 2H), 3.59
(dd, 1H, J ) 10.8, 3.5 Hz), 3.75 (dd, 1H, J ) 10.8, 10.8 Hz),
5.87 (s, 2H), 6.18 (dd, 1H, J ) 8.5, 2.5 Hz), 6.38 (d, 1H, J )
2.5 Hz), 6.63 (d, 1H, J ) 8.5 Hz), 6.96 (dd, 2H, J ) 8.6, 8.6
Hz), 7.16 (dd, 2H, J ) 8.6, 5.6 Hz); 13C NMR (CDCl3) δ 163.29,
159.39, 154.48, 148.111, 141.39, 140.73, 140.68, 129.47, 129.28,
115.32, 114.99, 107.85, 105.53, 101.05, 97.98, 71.33, 62.73,
59.48, 50.89, 41.45, 41.11, 36.12, 29.43, 28.48. The product
was converted to the D-tartrate salt. Recrystallization from
EtOH/Et2O gave a hygroscopic off-white solid: mp 84 °C
(fusion); 1H NMR (CD3OD) δ 1.82 (m, 1H), 2.07-2.19 (m, 2H),
2.30-2.76 (m, 4H), 2.82 (s, 3H), 3.02-3.15 (m, 1H), 3.76 (m,
2H), 3.96 (m, 2H), 5.87 (s, 2H), 6.30 (dd, 1H), 6.51 (d, 1H),
3â-(4-Flu or oph en yl)-2â-[[3,4-(m eth ylen edioxy)ph en oxy]-
m eth yl]n or tr op a n e [(1R)-2â,3â-4a ]. Meth od A. Purifica-
tion afforded 0.083 g (62%) of the product as a pink oil: 1H
NMR (C5D5N) δ 1.67 (dd, 1H, J ) 12.0, 3.5 Hz), 1.91 (m, 2H),
2.05 (ddd, 1H, J ) 13.9, 10.9, 1.9 Hz), 2.15 (m, 3H), 2.93 (dd,
1H, J ) 12.3, 1.9 Hz), 3.28 (dd, 1H, J ) 12.3, 5.5 Hz), 3.32 (m,
1H), 3.60 (dd, 1H, J ) 10.6, 6.2 Hz), 4.55 (ddd, 1H, J ) 9.5,
5.5, 1.9 Hz), 5.93 (s, 2H), 6.58 (dd, 1H, J ) 8.4, 2.4 Hz), 6.86
(d, 1H, J ) 8.4 Hz), 6.87 (d, 1H, J ) 2.4 Hz), 7.06 (dd, 2H, J
) 8.7, 8.7 Hz), 7.49 (dd, 2H, J ) 8.7, 5.4 Hz); 13C NMR (CDCl3)
δ 163.18, 159.29, 152.51, 148.34, 142.14, 141.93, 129.11,
128.99, 115.40, 115.06, 108.42, 108.10, 1010.18, 99.82, 83.05,
47.72, 46.21, 42.18, 39.84, 33.54, 31.31, 27.02. The product
was converted to the D-tartrate salt. Recrystallization from
EtOH/Et2O gave a white hygroscopic powder: mp 183-185
°C dec; 1H NMR (CD3OD) δ 1.98-2.37 (m, 7H), 3.24-3.42 (m,
2H), 3.72 (m, 1H), 3.87 (br s, 1H), 4.42 (s, 2H), 4.55 (bs, 1H),
5.7 (s, 2H), 6.39 (dd, 1H), 6.58 (d, 1H), 6.68 (d, 1H), 7.05 (m,
6.65 (d, 1H), 7.07 (m, 2H), 7.35 (m, 2H); [R]25 -48.3° (c 0.29,
D
CH3OH). Anal. (C26H30FNO9‚0.5H2O) C, H, N.
(1S)-3â-(4-F lu or op h en yl)-2â-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]tr op a n e [(1S)-2â,3â-7d ]. Fractions were
pooled to give 1.02 g (69%) of the pure product. 1H and 13C
NMR are identical with the (1R)-enantiomer. The product was
converted to the D-tartrate salt. Recrystallization from 2-pro-
panol/ethyl ether yielded a white powder: mp 90 °C (fusion);
1H and 13C NMR are identical with those of the (1R)-
enantiomer; [R]D -26.8° (c 0.63, CH3OH). Anal. (C26H30FNO9)
C, H, N.
2H), 7.33 (m, 2H); [R]23 +10.6° (c 0.36, CH3OH). Anal.
D
(C25H28FNO9) C, H, N.
(1R)-3â-(4-F lu or op h en yl)-2r-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]n or tr op a n e [(1R)-2r,3â-4b]. Meth od A.
Fractions were pooled to afford 0.19 g (55%) of pink oil: 1H
NMR (C5D5N) δ 1.68 (m, 3H), 1.78 (m, 1H), 1.87 (ddd, 1H, J )
12.6, 12.6, 2.2 Hz), 1.97 (m, 1H), 2.58 (m, 1H), 2.73 (ddd, 1H,
J ) 11.9, 11.9, 5.5 Hz), 3.58 (ddd, 1H, J ) 6.6, 3.2, 3.2 Hz),
3.69 (s, 1H), 3.71 (d, 1H, J ) 1.9 Hz), 3.96 (dd, 1H, J ) 6.4,
2.2 Hz), 5.90 (s, 2H), 6.32 (dd, 1H, J ) 8.3, 2.5 Hz), 6.62 (d,
1H, J ) 2.5 Hz), 6.78 (d, 1H, J ) 8.3 Hz), 7.11 (dd, 2H, J )
8.7, 8.7 Hz), 7.32 (dd, 2H, J ) 8.7, 5.5 Hz); 13C NMR (CDCl3)
δ 163.96, 159.66, 154.13, 148.14, 141.57, 138.91, 129.10,
128.98, 115.66, 115.33, 107.81, 105.44, 101.08, 97.91, 68.57,
56.35, 55.16 46.48, 46.21, 41.24, 37.89, 28.98, 24.99. The
product was converted to the D-tartrate salt. Recrystallization
from MeOH/Et2O gave a hygroscopic light yellow powder: mp
(1S)-3â-(4-F lu or op h en yl)-2r-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]tr op a n e [(1S)-2r,3â-7e]. Fractions were
pooled to give 0.76 g (64%) of the product as a slightly yellow
oil. 1H and 13C NMR are identical with those of the (1R)-
enantiomer. The compound was converted to the D-tartrate
salt. Recrystallization from MeOH/Et2O gave a hygroscopic
off-white powder: mp 95 °C (fusion); 1H and 13C NMR are
identical with the (1R)-enantiomer; [R]25 -50.8° (c 0.50,
D
CH3OH). Anal. (C26H30FNO9) C, H, N.
(1S)-3r-(4-F lu or op h en yl)-2â-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]tr op a n e [(1S)-2â,3r-7f]. Fractions were
pooled to give 0.24 g (32%) of the product as a light yellow oil.
1H and 13C NMR are identical with those the (1R)-enantiomer.
The product was converted to the D-tartrate salt. Recrystal-
lization from MeOH/Et2O gave a hygroscopic white solid: mp
56 °C dec. 1H and 13C NMR are identical with the those of
1
140 °C (fusion); H NMR (CD3OD) δ 1.88-2.45 (m, 6H), 2.66
(m, 1H), 3.00 (m, 1H), 3.53-3.70 (m, 2H), 4.13 (m, 1H), 4.28
(1R)-enantiomer, [R]25D +38.2° (c 0.33, CH3OH). Anal. (C26H30
FNO9‚0.25H2O) C, H, N.
-
(m, 1H), 4.42 (s, 2H), 5.84 (s, 2H), 6.14 (dd, 1H), 6.34 (d, 1H),
6.60 (d, 1H), 7.06 (m, 2H), 7.33 (m, 2H); [R]25 +36.0° (c 0.30,
D
CH3OH). Anal. (C25H28FNO9‚0.5H2O) C, H, N.
Gen er a l P r oced u r e for Dem eth yla tion of 3-(4-F lu or o-
p h e n y l)-2-[[3,4-(m e t h y le n e d io x y )p h e n o x y ]m e t h y l]-
tr op a n e (7). Meth od A. The appropriate isomer of 7 (1.0
mmol) was dissolved in 15 mL of dichloroethane under
nitrogen gas. Proton Sponge [1,8-bis(dimethylamino)naph-
thalene, 0.14 mmol; Aldrich] was added, and the solution was
stirred for 0.5 h at room temperature. ACE-Cl (6.0 mmol) was
added, and the reaction mixture was refluxed for 24 h. The
reaction mixture was cooled and the solvent removed under
reduced pressure. MeOH (10 mL) was added, and the reaction
mixture was refluxed for 24 h. The solvent was removed under
reduced pressure to afford a dark orange/red oil. Water was
added, and the reaction mixture was basified with NH4OH.
The aqueous layer was extracted with CH2Cl2. The solvent
was removed under reduced pressure, and the product was
purified by flash chromatography
(1R)-3r-(4-F lu or op h en yl)-2â-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]n or tr op a n e [(1R)-2â,3r-4c]. Meth od A.
Fractions were pooled to afford 0.069 g (55%) of yellow oil: 1H
NMR (C5D5N) δ 1.51 (m, 1H), 1.65 (m, 2H), 1.92 (m, 2H), 2.23
(ddd, 1H, J ) 13.8, 9.1, 7.4 Hz), 2.80 (ddd, 1H, J ) 11.1, 11.1,
7.4 Hz), 3.52 (m, 2H), 3.71 (d, 1H, J ) 3.3 Hz), 3.75 (dd, 1H,
J ) 9.1, 3.7 Hz), 3.91 (dd, 1H, J ) 9.1, 9.1 Hz), 5.85 (s, 2H),
6.35 (dd, 1H, J ) 8.4, 2.3 Hz), 6.65 (d, 1H, J ) 2.4 Hz), 6.77
(d, 1H, J ) 8.5 Hz), 7.09 (dd, 1H, J ) 8.6 Hz), 7.25 (dd, 1H, J
) 8.4, 5.6 Hz); 13C NMR (CDCl3) δ 163.61, 154.52, 148.07,
141.62, 140.39, 129.47, 115.37, 115.03, 107.87, 105.60, 101.08,
98.03, 71.11, 55.25, 51.96, 49.84, 39.12, 35.92, 34.33, 32.30.
The product was converted to the D-tartrate salt. Recrystal-
lization from 2-propanol/Et2O gave a hygroscopic white crys-
talline solid: mp 174 °C dec; 1H NMR (CD3OD) δ 1.72 (m, 1H),

Tropane Ring Analogues of Paroxetine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 255
2.01-2.24 (m, 5H), 2.58 (m, 1H), 2.94 (m, 1H), 3.69 (m, 2H),
(1S)-2-Ca r b om et h oxy-3-[[(t r iflu or om et h yl)su lfon yl]-
oxy]tr op en e (12). Carbomethoxytropinone19,40,43 (6.01 g, 30.5
mmol) was dissolved in 150 mL of anhydrous THF under N2.
After the mixture was cooled to -78 °C, bis(trimethylsilyl)-
amide (1.0 M solution in THF, 40.0 mL, 40.0 mmol) was added
dropwise by an addition funnel. The mixture was stirred at
-78 °C for 0.5 h. The triflimide (13.03 g, 36.5 mmol) was
dissolved in 100 mL of anhydrous THF and added dropwise.
The reaction was stirred for 10 min at -78 °C, then warmed
to 0 °C, and stirred for 2 h. The reaction vessel was fitted
with a drying tube and allowed to remain at 5 °C for 36 h.
The reaction was quenched with H2O and extracted with
CH2Cl2. After the mixture was dried over Na2SO4, solvent was
removed from the solution to afford 11.77 g of brown oil.
Purification by flash chromatography (hexane/EtOAc, 3:2) gave
8.07 g (80%) of triflate 12 as a golden oil: 1H NMR (CDCl3) δ
1.60 (m, 1H), 2.00 (m, 2H), 2.20 (m, 2H), 2.40 (s, 3H), 2.85 (m,
1H), 3.43 (m, 1H), 3.82 (s, 3 H), 3.93 (d, 1H); 13C NMR (CDCl3)
δ 163.79, 149.10, 125.19, 118.21 (q), 60.08, 57.40, 52.05, 34.86,
4.11 (m, 2H), 5.86 (s, 1H), 62.8 (dd, 1H), 6.50 (d, 1H), 6.65 (d,
1H), 7.06 (m, 2H), 7.33 (m, 2H); [R]23 -79.7° (c 0.32, CH3-
D
OH). Anal. (C25H28FNO9) C, H, N.
(1S)-3â-(4-F lu or op h en yl)-2â-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]n or tr op a n e [(1S)-2â,3â-4d ]. Meth od B.
Flash chromatography gave 0.098 g (26%) of the product.
Another fraction contained 0.118 g of the N-methyl starting
material. 1H and 13C NMR are identical with the (1R)-
enantiomer. The product was converted to the L-tartrate salt.
Recrystallization from EtOH/Et2O gave a light tan hygroscopic
1
powder: mp 180-184 °C dec; H and 13C NMR are identical
with those of the (1R)-enantiomer; [R]25 -10.3° (c 0.30,
D
CH3OH). Anal. (C25H28FNO9) C, H, N.
(1S)-3â-(4-F lu or op h en yl)-2r-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]n or tr op a n e [(1S)-2r,3â-4e]. Meth od A.
Fractions were pooled to afford 0.135 g (40%) of pink oil. 1H
and 13C NMR are identical with those of the (1R)-enantiomer.
The product was converted to the d-tartrate salt. Recrystal-
lization from MeOH/Et2O gave a hygroscopic tan powder: mp
34.66, 33.03, 29.96; [R]23 -7.8° (c 1.0, CHCl3). Anal.
D
(C11H14F3O5S) C, H, N.
1
170 °C (fusion); H and 13C NMR are identical with those of
the (1R)-enantiomer: [R]25 -52.4° (c 0.50, CH3OH). Anal.
(1S)-An h yd r oecogn in e Meth yl Ester (13). The triflate
12 (11.36 g, 34.5 mmol) was dissolved in 250 mL of anhydrous
THF under N2. Next, Pd(OAc)2 (0.177 g, 0.788 mmol), PPh3
(0.461 g, 1.76 mmol), and Et3N (14.4 mL, 10.45 g, 103.3 mmol)
were added. The reaction was stirred for 5 min, HCO2H (2.60
mL, 3.17 g, 68.9 mmol) was added dropwise, and the mixture
was refluxed for 1 h. After to room temperature, water was
added. The reaction was extracted with CHCl3 and dried over
Na2SO4. Purification by flash chromatography (Et2O/Et3N/
hexane, 9:1:10) gave 5.43 g (87%; 75%, 2 steps from 11) of 13:
1H NMR (CDCl3) δ 1.49 (m, 1H), 1.86 (m, 2H), 2.14 (m, 2H),
2.34 (s, 3H), 2.62 (m, 1H), 3.24 (m, 1H), 3.74 (s, 3H), 3.79 (m,
1H), 6.82 (m, 1H); [R]25 +35.5° (c 1.0, CHCl3) [lit.43 [R]25
D
(C25H28FNO9‚0.25H2O) C, H, N.
(1S)-3r-(4-F lu or op h en yl)-2â-[[3,4-(m et h ylen ed ioxy)-
p h en oxy]m eth yl]n or tr op a n e [(1S)-2â,3r-4f]. Meth od B.
Flash chromatography afforded 0.095 g (55%) of the product
as a brown oil. 1H and 13C NMR are identical with those of
the (1R)-enantiomer. The product was converted to the
L-tartaric acid salt. Recrystallization from EtOH/Et2O gave
1
a light tan hygroscopic powder: mp 163-166 °C dec; H and
13C NMR are identical with those of the (1R)-enantiomer; [R]25
D
+76.3° (c 0.27, CH3OH). Anal. (C25H28FNO9‚0.5H2O) C, H,
N.
D
D
(1R)-3r-(4-F lu or op h en yl)-2r-(3-m eth yl-1,2,4-oxa d ia zol-
5-yl)tr op a n e (10). To a cooled solution (-78 °C) of bromo-
fluorobenzene (0.64 g, 3.66 mmol) in 10 mL of anhydrous Et2O
was added t-BuLi (1.0 M in pentane, 6.0 mL, 6.00 mmol)
dropwise. After the mixture was stirred for 20 min at -78
°C, a solution of 9 (0.31 g, 1.51 mmol) in 20 mL of Et2O was
added slowly. The reaction was stirred at -78 °C for 2 h and
then at -40 °C for 1 h. The reaction was treated with ethereal
TFA over 5 min, allowed to warm to 0 °C, and diluted with
ether. The mixture was basified with dilute NH4OH and the
layers were separated. After the organic layer was dried over
Na2SO4, the solvent was removed to give 0.44 g of oil. Flash
chromatography [EtOAc/Et3N/hexanes (27:3:70)] gave 0.28 g
of product as a white solid. Recrystallization from hexanes
+38.3° (c 1.0, CH3OH)].
(1S)-3â-(4-F lu or op h en yl)t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester [(1S)-2â,3â-5]. The synthesis of this compound
has been described previously.43 The fractions were pooled to
give 4.22 g (51%) of product as a white solid: mp 92-93 °C
(lit.43 mp 94-96 °C). A second fraction (1.48 g) contained the
R-isomer: 1H NMR (CDCl3) δ 7.22 (m, 2H), 6.95 (m, 2H), 3.57
(m, 1H), 3.50 (s, 3H), 3.36 (m, 1H), 2.95 (m, 1H), 2.86 (m, 1H),
2.57 (m, 1H), 2.22 (s, 3H), 2.15 (m, 2H), 1.57-1.75 (m, 3H);
[R]25 +49.2° (c 0.52, CH3OH) [lit.43 for the naphthalene-1,5-
D
disulfonate [R]24 +84.5° (c 1.0, H2O)].
D
(1S)-3â-(4-F lu or op h en yl)t r op a n e-2r-ca r b oxylic Acid
Meth yl Ester [(1S)-2r,3â-5]. A white solid was obtained
which was recrystallized to give white crystals: mp 68-70 °C
(lit.43 mp 71.5-73.5 °C); 1H NMR (CDCl3) δ 1.56-2.15 (m, 6H),
2.40 (s, 3H), 3.00-3.14 (m, 2H), 3.23 (m, 1H), 3.41 (m, 1H),
3.50 (s, 3H), 6.97 (m, 2H), 7.21 (m, 2H); 13C NMR (CDCl3) δ
173.30, 161.40 (d), 139.38, 129.19, 129.07, 115.30, 114.97,
63.62, 61.12, 51.49, 51.42, 39.65, 38.76, 36.14, 26.40, 23.20;
[R]23D -14.5° (c 0.55, CH3OH) [lit.43 [R]24D -1.2° (c 5.0, CHCl3)].
1
afforded 0.158 g (35%) of white crystals: mp 101-103 °C; H
NMR (CDCl3) δ 1.52-1.67 (m, 2H), 1.83-2.15 (m, 3H), 2.25
(s, 3H), 2.32 (s, 3H), 2.47 (m, 1H), 3.35 (m, 1H), 3.56 (m, 1H),
3.65 (m, 1H), 4.18 (m, 1H), 6.84 (m, 2H), 7.06 (m, 2H); 13C NMR
(CDCl3) δ 179.41, 166.49, 137.41, 129.28, 129.16, 114.89,
114.55, 62.24, 59.63, 44.31, 40.48, 35.33, 34.69, 28.39, 23.10,
11.49; [R]23 +52.0° (c 0.60, CHCl3). Anal. (C17H20FNO3) C,
D
H, N.
(1S)-2-Ca r bom eth oxy-3-(4-flu or op h en yl)tr op en e (14).
To a round-bottom flask was added the triflate 12 (1.51 g, 4.59
mmol), LiCl (0.402 g, 9.57 mmol), tris(dibenzilideneacetone)-
dipalladium(0) (0.170 g), Na2CO3 (2.0 M soln in H2O, 4.5 mL,
9.0 mmol), and diethoxymethane (10 mL). The mixture was
stirred vigorously, and (p-fluorophenyl)boronic acid (0.852 g,
6.08 mmol) was added. The reaction was refluxed and
monitiored by TLC (Et2O/Et3N, 9:1). After 1 h, the reaction
was filtered through Celite. Et2O and H2O were added, and
the mixture was basified to pH 10 with NH4OH. The layers
were separated, and the aqueous layer was extracted with
CHCl3. The organic layers were combined and dried over
Na2SO4. The solvent was removed from the dried solution to
afford a dark yellow oil. Purification of the residue by flash
chromatography (silica gel, Et2O/Et3N/hexane, 9:1:10) afforded
1.09 g (86%) of the tropene as a yellow oil which solidified upon
standing: mp 56-58 °C; 1H NMR (CDCl3) δ 7.13-6.97 (m, 4H),
3.85 (d, 1H), 3.50 (s, 3H), 3.35 (m, 1H), 2.74 (m, 1H), 2.44 (s,
3H), 1.94-2.24 (m, 4H), 1.64 (m, 1H); 13C NMR (CDCl3) δ
168.21, 162.12 (d), 142.77, 137.15, 131.02, 128.52, 128.40,
(1R)-3r-(4-Flu or oph en yl)-2â-car bom eth oxytr opan e [(R)-
2â,3r-5]. To a solution of nickel acetate (5.33 g, 21.43 mmol)
in 50 mL of MeOH was added slowly a slurry of NaBH4 (0.801
g, 21.43 mmol) in 25 mL of MeOH. A solution of the
oxadiazolyltropane 10 (1.29 g, 4.28 mmol) and HCl (12 N, 1.78
mL, 21.43 mmol) in 50 mL of MeOH was added slowly to the
black slurry. The reaction mixture was stirred at room
temperature for 2 h and then refluxed for 3 h. The reaction
mixture was cooled and then Et2O and saturated NaHCO3
were added. The reaction was basified with NH4OH to pH
10. The layers were separated, and the blue aqueous layer
was extracted with Et2O several times. The solvent was
removed to afford 1.03 g of clear oil: 1H NMR (C6D6) δ 1.03-
1.18 (m, 2H), 1.27-1.33 (m, 1H), 1.70-192 (m, 2H), 2.02 (s,
3H), 2.25 (m, 1H), 2.38 (m, 1H), 2.88 (m, 1H), 3.25 (s, 3H),
3.31 (m, 1H), 3.55-3.66 (m, 1H), 6.77 (m, 2H), 6.91 (m, 2H).
The ester was characterized as the D-tartrate salt:17 [R]24
D
-34.4° (c 0.54, CH3OH); mp 65 °C. Anal. (C20H26FNO8‚0.5
H2O) C, H, N.

256 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Keverline-Frantz
(14) Blough, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M. J .; Boja, J .
W.; Carroll, F. I. Synthesis and Transporter Binding Properties
of 3â-(4′-Alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-
2â-carboxylic Acid Methyl Esters: Serotonin Transporter Selec-
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octanes with High binding Affinities and Selectivities for the
Serotonin Transporter Site. J . Med. Chem. 1996, 39, 2554-2558.
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H.; Boja, J . W.; Kuhar, M. J . Synthesis, ligand binding, QSAR,
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W.; Kuhar, M. J . K.; Carroll, F. I. 3R-(4′-Substituted phenyl)-
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Synthesis of the 2â,3R- and 2â,3â-isomers of 3-(p-substituted
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185.
115.15, 114.81, 60.35, 57.45, 51.36, 37.82, 36.14, 34.21, 30.13;
[R]23 +61.7° (c 0.86, CHCl3). Anal. (C16H18FNO2) C, H, N.
D
(1S)-3r-(4-F lu or op h en yl)t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester [(1S)-2â,3r-5]. Tropene 14 (0.93 g, 3.38 mmol)
was dissolved in 5 mL of anhydrous MeOH under argon. After
the solution was heated to 40 °C, the SmI2 solution (0.1 M in
THF, 140 mL, 14.0 mmol) was added dropwise via syringe.
The mixture was stirred at 40 °C and monitored by TLC [Et2O/
Et3N (9:1)]. After 1.0 h, the reaction was quenched by the
dropwise addition of a 10% HCl solution. Water and Et2O
were added, and the mixture was basified to pH 11 with
NH4OH and filtered through Celite. Et2O and saturated
Na2S2O3 were added, and the layers were separated. The
aqueous layer was extracted with CHCl3. The organic layers
were combined and dried over Na2SO4. Solvent was removed
from the dried solution to afford a yellow oil. Purification of
the residue by flash chromatography (2.5% EtOH/CHCl3 and
Et2O/Et3N/hexane, 9:1:10) gave the desired 2â,3R isomer (45%)
along with 14% of the 2â,3â isomer: 1H NMR (CDCl3) δ 7.16
(m, 2H), 6.93 (m, 2H), 3.58 (s, 3H), 3.28 (m, 3H), 2.42 (m, 2H),
2.38 (s, 3H), 2.19 (m, 2H), 1.47-1.64 (m, 2H), 1.31 (m, 1H);
1H NMR (C6D6) δ 6.91 (m, 2H), 6.77 (m, 2H), 3.59 (m, 1H),
3.31 (m, 1H), 3.25 (s, 3H), 2.88 (m, 1H), 2.38 (m, 1H), 2.28 (m,
1H), 2.01 (s, 3H), 1.73-1.92 (m, 2H), 1.28 (m, 1H), 1.03-1.17
(m, 2H); 13C NMR (CDCl3) δ 175.34, 161.62 (d), 139.91, 129.43,
129.31, 115.49, 115.16, 63.38, 59.66, 57.03, 52.01, 41.29, 39.72,
35.99, 29.38, 29.26.
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The compound was characterized as the L-tartaric acid
salt: mp 90-95 °C (fusion); 1H NMR (CD3OD) δ 1.81 (m, 1H),
2.11 (m, 2H), 2.51 (m, 1H), 2.63 (m, 1H), 2.70 (m, 1H), 2.81 (s,
3H), 3.45 (m, 2H), 3.95 (m, 2H), 4.47 (s, 3H), 7.05 (m, 2H),
7.48 (m, 2H); [R]24 +47.8° (c 0.27, CH3OH). Anal. (C20H26
-
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D
FNO8‚H2O) C, H, N.
Ack n ow led gm en t. This work was supported in part
by the National Institute on Drug Abuse, Grant Number
DA05477.
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