Synthesis and transporter binding properties of 3β-[4′-(phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2&-carboxylic acid methyl esters: Evidence of a remote phenyl binding domain on the dopamine transporter

Article abstract of DOI:10.1021/jm020098n

A series of 4′-substituted 3β-phenyltropane-2β-carboxylic acid methyl esters were synthesized and evaluated for binding at the dopamine transporter (DAT) in order to better define the pharmacophore for the cocaine binding site on the DAT. Results from the

Full text of DOI:10.1021/jm020098n

J . Med. Chem. 2002, 45, 4029-4037
4029
Syn th esis a n d Tr a n sp or ter Bin d in g P r op er ties of 3â-[4′-(P h en yla lk yl,
-p h en yla lk en yl, a n d -p h en yla lk yn l)p h en yl]tr op a n e-2â-ca r boxylic Acid Meth yl
Ester s: Evid en ce of a Rem ote P h en yl Bin d in g Dom a in on th e Dop a m in e
Tr a n sp or ter
Bruce E. Blough,† Kathryn I. Keverline,† Zhe Nie,† Herna´n Navarro,† Michael J . Kuhar,‡ and F. Ivy Carroll*,†
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and Yerkes Regional
Primate Center, Emory University, 954 Gatewood Road Northeast, Atlanta, Georgia 30329
Received March 4, 2002
A series of 4′-substituted 3â-phenyltropane-2â-carboxylic acid methyl esters were synthesized
and evaluated for binding at the dopamine transporter (DAT) in order to better define the
pharmacophore for the cocaine binding site on the DAT. Results from the study of 3â-[(4′-
phenylalkyl)phenyl]tropane-2â-carboxylic acid methyl esters (5a -c and 6a ,b) revealed strong
evidence of a previously unknown remote binding domain. The 3â-[(4′-phenylethyl)phenyl]-
tropane-2â-carboxylic acid methyl ester (5a ), which has a two methylene linker between the
3â-phenyl group and the remote phenyl group, has an IC50 value of 5.14 nM at the DAT. The
3â-[4′-(benzyl)phenyl] and 3â-[4′-(phenylpropyl)phenyl] analogues 6b and 5b, respectively, are
102- and 68-fold less potent than 5a at the DAT. Compound 5a also has good affinity for the
serotonin and norepinephrine transporters (Ki ) 21 and 6.5 nM, respectively) and is thus a
nonselective monoamine uptake inhibitor. Electrostatic effects make a significant contribution
to the DAT binding affinity of the 3â-[(4′-phenylalkenyl)phenyl]tropane-2â-carboxylic methyl
esters (6c, 7a ,b, and 8) and 3â-[(4′-phenylalkynl)phenyl]tropane-2â-carboxylic acid methyl esters
(4a -e). However, the results from the DAT binding on these compounds suggest that there
may be another binding domain even further remote from the 4′-position on the 3â-phenyl
group. In both cases, steric barriers have to be overcome before potent binding to the DAT is
observed. 3â-(4′(3-Phenyl-1-propynyl)phenyl)tropane-2â-carboxylic acid methyl ester (4b), with
an IC50 value of 1.82 nM, was the most potent compound studied. This compound possessed Ki
values of 1.19 and 16.5 nM for the serotonin and norepinephrine transporter and is thus a
nonselective monoamine uptake inhibitor.
In tr od u ction
the 3-phenyltropane class of DAT uptake inhibitors has
higher affinity for the DAT than the cocaine (1) class.4
Previous SAR studies directed at the 3-phenyltropane
class of compounds have shown that the affinity and
selectivity of compounds for the DAT relative to the
serotonin and norepinephrine transporters (5-HTT and
NET) are dependent on the substituents and substitu-
tion pattern on the aromatic ring connected to the 3â-
position of the tropane ring.5 Early studies reported
from this laboratory showed that RTI-32 (2b) containing
a 4′-methyl aromatic substituent binds with good affin-
ity and moderate selectivity to the DAT.6 Later studies
showed that RTI-83 (2c) and RTI-282 (2d ), which
contain a larger ethyl and propyl group in the 4′-
position, caused significant loss in binding affinity at
the DAT.5,7 More recently, we reported that RTI-359
(2e), RTI-360 (2f), and RTI-281 (2g), which contain a
4′-vinyl, 4′-ethynyl, and 4′-propynyl group, respectively,
retain high potency for the DAT.5 The present study was
undertaken to further characterize the SAR of substit-
uents on the 3â-phenyl ring. Specifically, we present the
synthesis and monoamine transporter binding proper-
ties of a series of 4′-substituent analogues 3 where M
is a linker group between the 4′-position of the 3â-
phenyl group and a second phenyl group attached to the
terminal end of the linker group. Compounds were
investigated where M varied in size, length, and degree
Studies directed toward gaining a better understand-
ing of the pharmacology of cocaine (1) (Chart 1) are
necessary for the development of therapeutic agents for
combating addiction.1,2 Cocaine binds to a specific
recognition site on the dopamine transporter (DAT),
blocking the reuptake of dopamine into the presynaptic
neurons resulting in the accumulation of excess dopa-
mine in the synaptic gap.3 Characterization of this
recognition site through structure-activity relationship
(SAR) studies has provided insight into the role of the
DAT in the pharmacological properties of cocaine.4
These studies are an integral part of the design of
medications that might be useful for treating cocaine
abuse. The present study was undertaken to further
explore the SAR of 4′-substituents on the 3â-phenyl ring
of the 3-phenyltropane (2a ) class of monoamine uptake
inhibitors.
In contrast to cocaine (1), which has a 3â-benzoyloxy
substituent, the 3-phenyltropane (2a ) class of DAT
uptake inhibitors has an aromatic ring attached directly
to the 3-position on the tropane ring system.4 In general,
* To whom correspondence should be addressed. Tel: 919 541-6679.
Fax: 919 541-8868. E-mail: fic@rti.org.
† Research Triangle Institute.
‡ Emory University.
10.1021/jm020098n CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/06/2002

4030 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Blough et al.
Ch a r t 1
Sch em e 2
â-iodostyrene by lithiation with n-butyllithium followed
by the addition of zinc chloride. We are unsure whether
the zinc reagent formed improperly or if elimination of
the stilbene intermediate occurred in the presence of
palladium. Acetylenes 4a -c were then converted to the
4′-phenylalkyl analogues 5a -c by reduction with hy-
drogen in methanol using 10% palladium on carbon as
catalyst. Stille coupling of RTI-55 (9) with phenylzinc
chloride and benzyl- and 1-phenylethenylzinc bromide
yielded compounds 6a -c (Scheme 1).
Sch em e 1
The synthesis of the stilbene analogues 7a ,b was less
straightforward. Attempts to selectively reduce acety-
lene 4a to an olefin were unsuccessful, regardless of the
reduction conditions. The reduction always proceeded
to the fully saturated analogue 5c even when using
Lindlar’s catalyst. Direct coupling of 9 with (E)-â-
tributylstannylstyrene under several conditions using
different catalysts failed, commonly resulting in decom-
position of the tropane ring.
Fortunately, RTI-55 (9) coupled to (Z)-1,2-bistrimeth-
ylstannylethylene and (E)-1,2-bistributylstannylethyl-
ene forming the (Z)- and (E)-stannylolefins, 10a ,b,
which proved to be useful intermediates for the prepa-
ration of 7a ,b and 8 (Scheme 2). Initially, the reaction
mixture resulting from the synthesis of 10a was acidi-
fied with 1 M hydrochloric acid in order to extract
organic byproducts. This resulted in protonolysis of the
stannane 10a and the isolation of RTI-359 (2e). How-
ever, we found that treatment of the crude (Z)-stannyl-
olefin 10a with iodine in methylene chloride afforded a
50:50 mixture of (Z)/(E) iodoolefins, 11a ,b. Coupling the
mixture with phenylzinc chloride provided the desired
stilbenes, 7a ,b, which were separated via high-perfor-
mance liquid chromatography (HPLC).
of unsaturation (see structures 4a -e, 5a -c, 6a -c, 7a ,b,
and 8 in Schemes 1 and 2).
Ch em istr y
The 3-phenyltropane analogues, 4a -e, 5a -c, 6a -c,
7a ,b, and 8 (see Schemes 1 and 2), were all derived from
9 (RTI-55) via Stille or Sonogashira type coupling
reactions.8-10 Compounds 4a -e were synthesized by the
Sonogashira coupling of RTI-55 (9) with phenylacetyl-
ene, 1-phenylpropyne, 1-phenylbutyne, and 1-phenyl-
pentyne, respectively (Scheme 1). Compound 4a was
also unexpectedly obtained when 9 was coupled with
(E)-â-styrenylzinc chloride in tetrahydrofuran (THF)
using bis(triphenylphosphine)palladium(II)chloride. The
(E)-â-styrenylzinc chloride was made in situ from (E)-
Stannane 10b was converted to stilbene 7b by first
reaction with iodine, forming only (E)-iodoolefin 11b
followed by coupling with phenylzinc chloride. (E)-

Phenyl Binding Domain on the Dopamine Transporter
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 4031
Ta ble 1. 3â-Phenyltropane 2â-Carboxylic Acid Methyl Ester Analogues
IC50, nM (Ki, nM)
compd
Ar
DAT [3H]WIN 35,428
5-HTT [3H]paroxetine
NET [3H]nisoxetine
WIN 35,065-2 (2a )a
C6H5
23 ( 5
1960 ( 61 (178 ( 5.5)
240 ( 27 (21.8 ( 2.5)
28.4 ( 3.8 (2.58 ( 3.5)
70.4 ( 4 (6.40 ( 0.36)
9.5 ( 0.8 (0.86 ( 0.01)
4.4 ( 0.4 (0.40 ( 0.04)
15.7 ( 1.5 (1.43 ( 0.14)
11.4 ( 0.28 (1.04 ( 0.03)
0.80 ( 0.06 (0.07 ( 01)
11.4 ( 1.3 (1.05 ( 0.12)
345 ( 37 (31.4 ( 3.4)
920 ( 73 (55 ( 44)
60 ( 0.53 (36 ( 0.03)
3910 ( 381 (2360 ( 230)
3921 ( 130 (2360 ( 78)
78 ( 4.1 (47 ( 2.5)
83.2( 2.8 (50.1 ( 1.7)
820 ( 46 (494 ( 28)
1590 ( 93 (958 ( 56)
21.1 ( 1.0 (12.7 ( 0.60)
70.2 ( 6.3 (42.3 ( 3.8)
372 ( 21 (224 ( 13)
2ba
2cb
2d b
2eb
2fb
C6H4(4′-CH3)
1.71 ( 0.31
55 ( 2.1
C6H4(4′-C2H5)
C6H4(4′-C3H7)
C6H4(4′-CHdCH2)
C6H4(4′-CtCH)
C6H4(4′-CtCCH3)
C6H4(4′-CHdCHCH3)
2′-naphthyl
68.5 ( 7
1.24 ( 0.2
1.2 ( 0.1
2.37 ( 0.2
5.29 ( 0.5
0.51 ( 0.03
1.1 ( 0.09
5.17 ( 0.23
2gb
2h b
12
13c
15d
2′-naphthyl
2′-naphthyl
a
b
d
Taken from ref 6. Taken from ref 5. c This is the 2â,3R-isomer. This is 3-(2′-naphthyl)tropene-2-carboxylic acid methyl ester.
Sch em e 3
kis(triphenylphosphine)palladium(0) as catalyst gave
tropene 15. Reduction of 15 with samarium iodide at
-78 °C using methanol as the proton source followed
by quenching with trifluoroacetic acid gave the desired
12 along with the 2â,3R-isomer 13, which were sepa-
rated by column chromatography. A comparison of
the 1H NMR spectrum of 13 to other previously
reported 2â,3R-analogues12 suggests that this compound
exists largely in the boat conformation as shown in
Scheme 3.
Biology
The binding affinities of the compounds at the DAT,
5-HTT, and NET were determined via competition
binding assays using the previously reported proce-
dures.13 The final concentration of radioligands in the
assays was 0.5 nM [3H]WIN35,428 for the DAT, 0.2 nM
[3H]paroxetine for the 5-HTT, and 0.5 nM [3H]nisoxetine
for the NET.
Iodoolefin 11b was also coupled to benzylzinc chloride
in a similar fashion forming 8.
The olefin stereochemistry of styrenes 7a ,b was
1
verified by H NMR analysis. The olefin protons were
Resu lts a n d Discu ssion
observed as singlets in deuteriochloroform but nons-
inglets in d6 benzene. Unfortunately, the peaks were
buried within the aromatic region of the 1H NMR
spectrum making coupling constant analysis difficult.
Instead, the stereochemistry of the two analogues could
The results of the binding studies are summarized in
Tables 1 and 2 along with the results for 2a (WIN 35,-
065-2) and other previously reported compounds for
comparison. The original paper from our laboratory
concerning the SAR of the 3-phenyltropane class of
dopamine uptake inhibitors was directed toward ex-
plaining the effect of adding substituents to the 3â-
aromatic ring of the lead compound WIN 35,065-2.4 The
studies showed that substitution of the 4′-position with
both electron-donating and electron-releasing groups led
to compounds with high affinity for the DAT.14 Quan-
titative SAR (QSAR) and comparative molecular field
analysis (CoMFA) models were initially reported for 12
4′-substituted analogues14 and then for 25 4′-substituted
and 3′,4′-disubstituted WIN 35,065-2 analogues.4,7,14 The
classical QSAR models suggested that distribution
properties (hydrophobicity) were important contributors
to binding at the DAT. The CoMFA models showed that
some steric bulk extending from below and above the
4′-position contributes to enhanced potency, although
excessive bulk led to reduced potency. In addition, the
model suggests that electrostatic forces account for
approximately one-quarter of the binding affinity and
thus may make a significant contribution to potency.
1
be correlated with the H shifts of the known (Z)- and
(E)-stilbene olefin singlets. The (Z)- and (E)-stilbene
olefin singlets appear at 6.56 and 7.08 ppm, respectively.
The resonances for the olefin protons of 7a ,b come at
6.53 and 7.06 ppm, respectively, and are clearly cor-
related.
The synthetic results provide additional evidence for
the structural assignments. Conversion of (E)-stannane
10b to (E)-iodoolefin 11a occurred with >99% retention
of stereochemistry while the conversion of less thermo-
dynamically stable (Z)-stannane 10a to (Z)-iodoolefin
11a occurred with only a 50% retention of stereochem-
istry. One would not expect the (Z)-stannane to fully
retain its stereochemistry and the (E)-stannane to
partially isomerize.
To gain information about the steric effect on DAT
affinity, 3â-(2′-naphthyl)tropane-2â-carboxylic acid meth-
yl ester (12) was prepared by the route shown in Scheme
3. Treatment of the triflate 1411 with 2-naphthylboronic
acid in refluxing diethoxymethane (DEM) using tetra-

4032 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Blough et al.
Ta ble 2. 3â-Phenyltropane 2â-Carboxylic Acid Methyl Ester Analogues with Linkers
a
Compound 4e has a -CtC-(CH2)4OH substituent at the 4-position.
Later studies demonstrated that a large, bulky sub-
stituent at the 4-position of the aromatic ring of 3-phe-
nyltropane analogues hinders binding to the DAT.4,5,7
As shown in Table 1, RTI-83 (2c) and RTI-282 (2d ),
which have a 4′-ethyl and a 4′-propyl substituent,
respectively, were reported to have IC50 values of 55 and
69 nM. Yet their sizes were only slightly larger than
the 4′-methyl analogue RTI-32 (2b), which had an IC50
value of 1.71 nM. Thus, exchanging one of the hydrogens
on the 4′-methyl group of RTI-32 with a methyl or ethyl
group to give RTI-83 and RTI-282 resulted in a 32- and
40-fold loss in binding potency, respectively. These
results suggest that as the substituent increases in size,
the potency decreases. However, in contrast, 2e (RTI-
359) and 2f (RTI-360), which have a two carbon vinyl
and acetylenic group conjugated to the tropane phenyl
group, show IC50 values of 1.24 and 1.2 nM, respec-
tively.5 Compounds RTI-282 (2d ), RTI-281 (2g), and
RTI-296 (2h ), which possess linearly oriented three
carbon atom 4′-substituents, show increased binding
affinity at the DAT as the degree of unsaturation
increases with the propyl, propenyl, and propynyl
analogues, 2d ,h ,g, showing IC50 values of 65.8, 5.29, and
2.37 nM, respectively.
However, adding three additional methylene groups to
4a to give analogue 4d decreases binding affinity 2
orders of magnitude to an IC50 value of 300 nM.
Interestingly, replacing the terminal phenyl group in
4a with a hydroxybutyl group to give 4e, a more polar
substituent further removed from the acetylene moiety,
causes an order of magnitude decrease in binding
affinity (IC50 ) 57 nM).
A comparison of compounds 7a ,b possessing an ole-
finic linker reveals that the (E)-isomer 7b with an IC50
value of 3.09 nM is about four times as potent as the
(Z)-isomer 7a , which has an IC50 value of 11.7 nM.
Lengthening the olefinic group of 7b by one methylene
to give compound 8 resulted in a 5-fold decrease in
affinity. These results fall within the length constraints
observed for the acetylenes. Compound 6c with a one
carbon linker possessing an exo-methylene group gave
an IC50 value of 474 nM.
Compounds 5a -c and 6b contain a second phenyl
group linked by methylene spacers of increasing length.
The biphenyl analogue 6a with no spacer has an IC50
value of 15.6 nM. Analogues 6b and 5b,c which possess
one, three, and four methylenes between the two phenyl
rings, all showed very low affinity for the DAT: IC50
values of 228-526 nM. Surprisingly, compound 5a ,
which contains a two methylene linker connecting the
remote phenyl group to the tropane phenyl ring, binds
to the DAT with an IC50 value of 5.14 nM. These results,
particularly the 102-fold increase in binding affinity in
going from the one methylene linker analogue 6b to the
two methylene linker analogue 5a , suggest that a
remote binding site exists in the DAT binding domain
extended out approximately two carbons from the
tropane 3â-phenyl ring. This spatial region is somewhat
confined and apparently ends abruptly as evidenced by
Table 2 lists the monoamine transporter binding
properties of a number of compounds where M repre-
sents linkers of different types between the 4′-position
on the tropane 3â-aryl ring to a second aromatic ring
or in the case of 4e a hydroxyl group. Several points
are evident from the binding data. Comparing the
acetylene analogues 4a -e shows that adding one me-
thylene to the acetylenic moiety of 4a to give analogue
4b results in only a small increase of binding affinity,
1.82 vs 3.7 nM. Whereas, adding two methylenes to give
4c results in a small decrease in binding affinity.

Phenyl Binding Domain on the Dopamine Transporter
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 4033
the dramatic loss of binding affinity of 5b,c, which
possesses one and two additional methylene groups
between the phenyl groups. This suggestion of a remote
DAT binding domain is supported by comparing the
binding affinities of 5a and 6b to those of 2c (RTI-83)
and 2b (RTI-32). Thus, replacement of one of the methyl
hydrogens of 2b with a phenyl group to give 6b results
in a 300-fold loss of affinity (1.71 vs 526 nM); whereas,
replacement of one of the methyl hydrogens of 2c with
a phenyl group to give 5a results in a 11-fold increase
in affinity (55 vs 5.14 nM).
of 16.5 and 6.50, respectively, were the only two
analogues to show good affinity for the NET. Other
analogues showed Ki values between 25 and 1800 nM.
Because compounds 4b and 5a possess high affinity for
all three transporters, they are nonselective monoamine
uptake inhibitors. Compound 4a has good affinity for
both the DAT and 5-HTT with much weaker NET
affinity and is thus a DAT/5HTT selective uptake
inhibitor.
In summary, we provide evidence of a previously
unknown remote cavity or binding domain on the DAT.
Regions close to the 4-position of the 3â-phenyl group
are also bounded by a steric barrier, which must be
overcome before potent binding occurs. The exact nature
of the domain and whether binding in the area affects
transporter function are unknown. Additional experi-
ments are being conducted to probe the site further and
also examine whether the C2 and C3 open domains are
connected.
Compounds 4a -d , 7a ,b, and 8 possess an acetylenic
and olefinic group, respectively, conjugated to the 4′-
phenyl on the tropane ring. The analogues 4a -c, 7a ,b,
and 8 have IC50 values at the DAT of 1.82-15.8 nM.
The relatively high DAT binding affinity of these
analogues could be due to electronic contribution from
the conjugated acetylenic and olefinic group or to
interaction with remote binding sites or both. Regard-
less of the reason for the high DAT binding affinity, a
comparison of 4c (IC50 ) 6.28) to 4d (IC50 ) 300) shows
that the extension of the linker of 4c by one methylene
group to give 4d results in a 48-fold loss in binding
affinity. Thus, there appears to be a steric barrier to
binding if the linker M is longer than five carbon atoms.
Compounds 6b,c both of which have a one carbon linker
between the two phenyl rings, show very low affinity
for the DAT.
Exp er im en ta l Section
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on either a 250 MHz (Bruker AM-250) or a 300 MHz
(Bruker AVANCE 300) spectrometer. Chemical shift data for
the proton resonances were reported in parts per million (δ)
relative to internal (CH3)4Si (δ 0.0). Optical rotations were
measured on an AutoPol III polarimeter, purchased from
Rudolf Research. Elemental analyses were performed by
Atlantic Microlab, Norcross GA. Analytical thin-layer chro-
matography (TLC) was carried out on plates precoated with
silica gel GHLF (250 µm thickness). TLC visualization was
accomplished with a UV lamp. All moisture sensitive reactions
were performed under a positive pressure of nitrogen main-
tained by a direct line from a nitrogen source. HPLC separa-
tions were performed on a Rainen Rabbit-HP instrument using
a Dynamax-60A semiprep column.
The binding data listed in Table 2 for the acetylenic
compound, 4a , and the olefinic, 7a ,b, all of which have
two carbon linkers, also indicate that a moderate steric
barrier exists adjacent to the tropane phenyl ring, which
limits the binding affinity of compounds. The binding
affinity is ordered as follows: alkyne (4a ) ) (E)-alkene
(7b) > (Z)-alkene (7a ). This steric barrier is also evident
in 6b,c both of which possess a one carbon linker
between the two phenyl groups. Support for this notion
may also be found by the observation that a large, flat
3â-(2′ naphthyl) group binds with high potency to the
DAT, as shown by the IC50 value of 0.51 nM for
compound 12. It is interesting to note that the 3R-(2′-
naphthyl)tropane 13 with a IC50 value of 1.1 nM is
highly potent at the DAT. Even the 2-tropene analogue
15 with an IC50 value of 5.17 nM has reasonable affinity
for the DAT. Because Davis et al.15,16 reported that 3â-
(2-naphthyl)2-â-acetyltropane also possessed high af-
finity for the DAT, the increase in affinity is not
dependent on the 2â-ester group.
Previous studies have shown that the size and type
of 2â-group has very little effect on the binding affinity
of 3â-phenyl-2â-substituted tropane analogues.4 These
results suggest that there is a large open domain
extending out from the C2 position on the tropane ring,
which has little effect on binding to the DAT. The
present studies on the 3â-(4′-substituted phenyl)-2â-
carboxylic acid methyl ester analogues show that there
are binding domains extending out from the 4′-position
on the 3â-phenyl ring. However, in contrast to the 2â-
position, these binding domains are highly specific.
THF was distilled just prior to its use (sodium benzophenone
ketyl) or was purchased dry from J . T. Baker (dispensed from
a Ultralow Water cylinder). Anhydrous methylene chloride,
toluene, and ethyl acetate were purchased from Aldrich
Chemical Co. Triethylamine and diisopropylamine were dis-
tilled from CaH2 and stored.
3â-(4′-P h en yleth yn ylph en yl)tr opan e-2â-car boxylic Acid
Meth yl Ester (4a ). To a solution of 0.302 g (0.783 mmol) of
3â-(4′-iodophenyl)tropane-2â-carboxylic acid methyl ester (9,
RTI-55) in 8 mL of degassed diisopropylamine under nitrogen
was added 55 mg (0.078 mmol) of bis(triphenylphosphine)-
palladium(II)chloride and 15 mg (0.078 mmol) of copper(I)
iodide. To this yellow slurry was added 0.084 g (0.823 mmol)
of phenylacetylene. The solution darkened almost immediately
and was stirred for 8 h. The reaction was quenched with
saturated aqueous ammonium chloride. To this mixture were
added ether and a small amount of ammonium hydroxide and
stirred overnight. The aqueous layer turned blue, and the
copper salts disappeared. The free base was extracted from
the aqueous layer with methylene chloride. The combined
organic layers were concentrated in vacuo. The product was
partially purified by dissolving the crude product in diethyl
ether, adding 1 M HCl until acidic, and extracting the aqueous
layer with diethyl ether. The remaining aqueous layer was
cooled to 0 °C by adding ice and then basified by the addition
of ammonium hydroxide with stirring until cloudiness per-
sisted. The free base was extracted from the aqueous layer by
first stirring at room temperature with methylene chloride for
1 h and then extracting with methylene chloride. The combined
organic layers were concentrated in vacuo. The resulting
yellow oil was purified by flash chromatography on silica gel,
eluting with ethyl acetate-hexane (75:25) with the addition
of 2% triethylamine to give 0.255 g (91%) of 4a . 1H NMR
(CDCl3): δ 1.71 (m, 3H), 2.15 (m, 2H), 2.25 (s, 3H), 2.58 (dt,
1H, J ) 2.7, 12.2 Hz), 2.92 (bs, 1H), 3.0 (m, 1H), 3.36 (bs, 1H),
Examination of the 5-HTT binding affinity data in
Table 2 shows that 4a ,b and 6a with Ki values of 4.3,
1.19, and 8.7 nM, respectively, possess high affinity for
the 5-HTT. Other analogues show Ki values between
21.3 and 439 nM. Compounds 4b and 5a with Ki values

4034 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
3.49 (s, 3H), 3.57 (bs, 1H) 7.2-7.58 (m, 9H). The free base was
Blough et al.
3.70 (bs, 2H), 7.16 (d, 2H, J ) 10.4 Hz), 7.29 (d, 2H, J ) 10.5
Hz). The free base was converted to the hydrochloride salt;
[R]D24 -85.4° (c 0.12, CH3OH). Anal. (C22H30NClO3‚0.5H2O) C,
H, N.
24
converted to the (D)-tartrate salt: [R]D -109.1° (c 0.05, CH3-
OH). Anal. (C28H31NO8‚1.5H2O) C, H, N.
3â-(4′-(3-P h en yl-1-pr opyn yl)ph en yl)tr opan e-2â-car box-
ylic Acid Meth yl Ester (4b). The procedure for 4a was
followed using 0.462 g (1.2 mmol) of 9 (RTI-55), 0.153 g (1.3
mmol) of 3-phenyl-1-propyne, and a catalytic amount of bis-
(triphenylphosphine)palladium(II)chloride and of copper(I)-
iodide to give 0.342 g (76%) of 4b. 1H NMR (CDCl3): δ 1.61
(m 3H), 1.87 (m 2H), 2.14 (s, 3H), 2.49 (t, 1H. J ) 12.5 Hz),
2.83 (bs, 1H), 2.89 (dd, 1H, J ) 5.3, 12.5 Hz), 3.28 (bs, 1H),
3â-(4′-(2-P h en yleth yl)ph en yl)tr opan e-2â-car boxylic Acid
Meth yl Ester (5a ). A solution of 0.255 g (0.71 mmol) of 4a in
4 mL of methanol was added to a slurry of a catalytic amount
of 10% palladium on carbon (fire hazard) in enough methanol
to cover the active catalyst. The gauge assembly on a Parr
hydrogenation apparatus was fitted on top, and the tube was
pressurized with 60 psi hydrogen gas. To ensure maximum
hydrogen content, the slurry was then evacuated using an
aspirator and then repressurized with hydrogen gas. This
procedure was repeated twice. The slurry was stirred for 0.5
h. The tube was vented, and the slurry was filtered through a
plug of Celite to remove the palladium on carbon and washed
with methylene chloride. The remaining solution was concen-
trated in vacuo. The resulting yellow oil was purified by flash
chromatography on silica gel. The oil was eluted with ethyl
acetate-hexane (75:25) with the addition of 2% triethylamine
3.41 (s, 3H), 3.48 (bs, 1H), 3.74 (s, 2H), 7.08-7.34 (m, 9H). 13
C
NMR (CDCl3): δ 25.1, 25.7, 25.9, 33.6, 33.7, 41.8, 51.2, 52.6,
62.2, 65.2, 82.8, 86.9, 121.0, 126.6, 127.2 (2C), 127.9 (2C), 128.5
(2C), 131.3 (2C), 136.8, 142.9, 172.0. The free base was
converted to the hydrochloride salt; mp 85-87 °C; [R]D20 -103°
(c 0.50, CH3OH). Anal. (C25H28ClNO2‚2.5H2O) C, H, N.
3â-(4′-(4-P h en yl-1-bu tyn yl)p h en yl)tr op a n e-2â-ca r box-
ylic Acid Meth yl Ester (4c). The procedure for 4a was
followed using 0.250 g (0.65 mmol) of 9 (RTI-55), 0.088 g (0.68
mmol) of 4-phenyl-1-butyne, 45 mg (0.065 mmol) of bis-
(triphenylphosphine)palladium(II)chloride, and 12 mg (0.065
1
to give 0.252 g (98%) of 5a . H NMR (CDCl3): δ 1.67 (m, 4H),
2.12 (m, 2H), 2.21 (s, 3H), 2.58 (t, 1H, J ) 12.2 Hz), 2.84 (s,
4H), 2.93 (m, 1H), 3.35 (bs, 1H), 3.48 (s, 3H), 3.52 (bs, 1H),
7.09 (d, 2H, J ) 8.1 Hz), 7.19 (d, 5H, J ) 8.7 Hz), 7.26 (d, 2H,
J ) 8.2 Hz). The free base was converted to the tosylate salt;
1
mmol) of copper iodide to give 0.253 g (100%) of 4c. H NMR
(CDCl3): δ 1.73 (m, 3H), 2.06 (m, 2H), 2.20 (s, 3H), 2.55 (dt,
1H, J ) 2.7, 12.5 Hz), 2.66 (t, 2H, J ) 7.4 Hz), 2.89 (t, 2H, 7.4
Hz), 2.86-2.97 (m, 2H), 3.33 (bs, 1H), 3.47 (s, 3H), 3.54 (bs,
1H), 7.13-7.32 (m, 9H). The free base was converted to the
(D)-tartrate salt; mp 82-84 °C; [R]D24 -87.4° (c 0.175, MeOH).
Anal. (C30H35NO8‚0.25H2O) C, H, N.
mp 117-119 °C; [R]D24 -73.6° (c 0.250, MeOH). Anal. (C31H37
-
NO5S) C, H, N.
3â-(4′-(3-P h en ylp r op yl)p h en yl)tr op a n e-2â-ca r boxylic
Acid Meth yl Ester (5b). The procedure for 5a was followed
1
using 0.202 g (0.5 mmol) of 4b to give 0.120 g (60%) of 5b. H
3â-(4′-(5-P h en yl-1-p en tyn yl)p h en yl)tr op a n e-2â-ca r box-
ylic Acid Meth yl Ester (4d ). The procedure for 4a was
followed using 0.378 g (0.98 mmol) of 9 (RTI-55), 0.141 g (1.18
mmol) of 5-phenyl-1-pentyne, and a catalytic amount of bis-
(triphenylphosphine)palladium(II)chloride and of copper(I)-
iodide to give 0.191 g (48%) of 4d as a solid. 1H NMR (CDCl3):
δ 1.64-1.71 (m, 3H), 1.90 (q, 2H, J ) 7.2 Hz), 2.0-2.3 (m,
2H), 2.22 (s, 3H), 2.34 (t, 2H, J ) 6.9 Hz), 2.56 (dt, 1H, J )
2.7, 12.3 Hz), 2.79 (t, 2H, J ) 7.5 Hz), 2.89 (m 1H), 2.98 (dt,
1H, J ) 5.1, 12.6 Hz), 3.36 (bs, 1H), 3.48 (s, 3H), 3.55 (bs, 1H),
7.17 (d, 2H, J ) 8.4 Hz), 7.20-7.33 (m 5H), 7.32 (d, 2H, J )
8.4 Hz). 13C NMR (CDCl3): δ 17.8, 18.0, 24.1, 24.9, 28.7, 29.4,
30.4, 32.6, 32.8, 33.8, 40.1, 50.1, 51.2, 61.2, 64.3, 80.2, 88.1,
120.3, 124.8, 126.2 (2C), 127.3 (2C), 127.5 (2C), 130.1 (2C),
NMR (CDCl3): δ 1.65 (m, 3H), 1.92 (p, 2H, J ) 7.8 Hz), 2.17
(m, 2H), 2.24 (s, 3H), 2.61 (q, 8.8 Hz), 2.61 (m, 1H), 2.89 (m,
1H), 2.98 (dt, 1H, J ) 5.2, 12.6 Hz), 3.37 (bs, 1H), 3.48 (s, 3H),
3.56 (bs, 1H), 7.08 (d, 2H, J ) 8.2 Hz), 7.17 (d, 5H, J ) 8.4
Hz), 7.3 (m, 2H). The free base was converted to the hydro-
24
chloride salt; mp 132-136 °C; [R]D -94.6° (c 0.35, MeOH).
Anal. (C25H32NClO2‚0.75H2O) C, H, N.
3â-(4′-(4-P h en ylb u t yl)p h en yl)t r op a n e-2â-ca r b oxylic
Acid Meth yl Ester (5c). The procedure for 5a was followed
using 0.695 g (0.18 mmol) of 4c to give 0.75 g (100%) of 5c. 1H
NMR (CDCl3): δ 1.63 (m, 7H), 2.07 (m, 2H), 2.29 (s, 3H), 2.88
(bs, 1H), 2.97 (dt, 1H, J ) 5.3, 12.8 Hz), 3.35 (bs, 1H), 3.48 (s,
3H), 3.55 (bs, 1H), 7.11 (d, 2H, J ) 8.1), 7.11-7.29 (m, 7H).
13C NMR (CDCl3): δ 25.1, 25.9, 31.0, 31.2, 33.4, 34.1, 35.4,
35.8, 42.0, 51.1, 52.8, 62.3, 65.4, 125.6, 127.2 (2C), 128.0 (2C),
128.2 (2C), 128.4 (2C), 139.9, 140.2, 142.6, 172.2. The free base
24
140.7, 141.7, 171.0; mp 106-108 °C; [R]D -41.0° (c 0.20,
MeOH). Anal. (C27H31NO2) C, H, N.
3â-(4′-(6′-H yd r oxy-1-h exyn yl)p h en yl)t r op a n e-2â-ca r -
boxylic Acid Meth yl Ester (4e). To a solution of 1.18 g (3.0
mmol) of 9 (RTI-55) in 3.0 mL of degassed triethylamine under
nitrogen was added a catalytic amount of bis(triphenylphos-
phine)palladium(II)chloride and of copper(I)iodide. To this
yellow slurry was added 0.72 g (3.7 mmol) of 1-tributylsiloxy-
5-pentyn-1-ol dissolved in degassed triethylamine. The solution
darkened almost immediately and was stirred for 48 h. The
reaction was quenched with saturated aqueous ammonium
chloride. To this mixture were added ether and a small amount
of ammonium hydroxide and stirred overnight. The aqueous
layer turned blue, and the copper salts disappeared. The free
base was extracted from the aqueous layer with methylene
chloride. The combined organic layers were concentrated in
vacuo.
The crude product was dissolved in 8 mL of THF. To this
mixture was added 3.3 mL (3.3 mmol) of 1.0 M tetrabutylam-
monium fluoride. The mixture was stirred for 2 h and was
complete. To this mixture was added water, and the aqueous
layer was extracted three times with ether. The combined
organic extracts were dried over sodium sulfate and concen-
trated in vacuo. The resulting yellow oil was purified by flash
chromatography on silica gel and was partially dissolved in
methylene chloride in order for the crude mixture to be applied
to the column. Elution with ethyl acetate-hexane (50:50) with
the addition of 5% triethylamine afforded 0.78 g (72%) of 4e.
1H NMR (CDCl3): δ 1.71 (m 7H), 2.17 (m, 2H), 2.21 (s, 3H),
2.44 (m, 2H), 2.54 (t, 1H, 12.4 Hz), 2.90 (bs, 1H), 2.97 (dd, 1H,
J ) 5.0, 12.4 Hz), 3.36 (bs, 1H), 3.48 (s, 3H), 3.55 (bs, 1H),
24
was converted to the (D)-tartrate salt; mp 97-99 °C; [R]D
-83.1° (c 0.160, MeOH). Anal. (C30H39NO8‚1H2O) C, H, N.
3â-(4′-Bip h en yl)t r op a n e-2â-ca r b oxylic Acid Met h yl
Ester (6a ). To a solution of 0.200 g (0.519 mmol) of 9 (RTI-
55) in 2.3 mL of dry degassed THF under nitrogen was added
phenylzinc chloride, made by reacting 0.164 mL (1.55 mmol)
of bromobenzene with 0.62 mL (1.55 mmol) of 2.5 M n-
butyllithium in THF and 3.1 mL (1.55 mmol) of 0.5 M zinc
chloride in THF, followed by a catalytic amount of bis-
(triphenylphosphine)palladium(II)chloride. The reaction dark-
ened immediately and was stirred overnight. To this mixture
was added water that formed a precipitate of zinc salts. The
solids were filtered leaving a biphasic mixture. The product
was partially purified by adding 1 M HCl until acidic and
extracting the aqueous layer with diethyl ether. The remaining
aqueous layer was cooled to 0 °C by adding ice and then
basified by the addition of ammonium hydroxide with stirring
until cloudiness persisted. The free base was extracted from
the aqueous layer by first stirring at room temperature with
methylene chloride for 1 h and then extracting as normal. The
combined organic layers were concentrated in vacuo. The
resulting yellow oil was purified by flash chromatography on
silica gel. Elution with ethyl acetate-hexane (75:25) with the
1
addition of 2% triethylamine afforded 0.078 g (45%) of 6a . H
NMR (CDCl3): δ 1.60-1.73 (m, 3H), 2.05-2.23 (m, 2H), 2.24
(s, 3H), 2.64 (dt, 1H, J ) 2.7, 12.6 Hz), 2.96 (m, 1H), 3.05 (dt,
1H, J ) 5.1, 12.6 Hz), 3.38 (bs, 1H), 3.52 (s, 3H), 3.59 (bs, 1H),
7.26-7.34 (m, 4H), 7.41 (t, 1H, J ) 7.5 Hz), 7.51 (d, 2H, J )

Phenyl Binding Domain on the Dopamine Transporter
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 4035
8.1 Hz), 7.57 (d, 2H, J ) 8.4 Hz). 13C NMR (CDCl3): δ 25.6,
26.3, 33.9, 34.5, 42.4, 51.5, 53.2, 62.7, 65.7, 127.0 (2C), 127.3,
127.4 (2C), 127.6 (2C), 128.1 (2C), 129.0, 139.0, 141.4, 142.6,
172.6. The free base was converted to the (D)-tartrate salt; mp
120-121 °C; [R]D24 -98.0° (c 0.150, MeOH). Anal. (C26H31NO8‚
0.25H2O) C, H, N.
remove the palladium. The solution was concentrated in vacuo
forming (Z)-stannane 10a .
The yellow oil was immediately dissolved in 7 mL of dry
methylene chloride, and 0.944 g (3.72 mmol) of iodine was
added to the solution. A dark precipitate formed. The slurry
was stirred until the iodine disappeared and then worked up
as before. The solution was concentrated in vacuo to remove
excess solvent. The product was partially purified by adding
1 M HCl until acidic and extracting the aqueous layer with
diethyl ether. The remaining aqueous layer was cooled to 0
°C by adding ice and then basified by the addition of am-
monium hydroxide with stirring until cloudiness persisted. The
free base was extracted from the aqueous layer by first stirring
at room temperature with methylene chloride for 1 h and then
extracting as normal. The combined organic layers were
concentrated in vacuo. The resulting yellow oil was purified
by flash chromatography on silica gel. Elution with ethyl
acetate-hexane (75:25) with the addition of 2% triethylamine
afforded a 50:50 mixture of the (Z)- and (E)-iodides 11a ,b. The
two iodides could not be separated on silica gel; thus, they were
used without further purification in the next reaction.
To a solution of the iodides in 4 mL of degassed THF under
nitrogen was added phenylzinc chloride, made by first reacting
1.55 mL (2.48 mmol) of 1.6 M phenyllithium in THF and 4.97
mL (2.48 mmol) of 0.5 M zinc chloride in THF, followed by a
catalytic amount of bis(triphenylphosphine)palladium(II)-
chloride. The reaction darkened immediately and was stirred
overnight. To this mixture was added water that formed a
precipitate of zinc salts. The solids were filtered leaving a
biphasic mixture. The product was partially purified by adding
1 M HCl until acidic and extracting the aqueous layer with
diethyl ether. The remaining aqueous layer was cooled to 0
°C by adding ice and then basified by the addition of am-
monium hydroxide with stirring until cloudiness persisted. The
free base was extracted from the aqueous layer by first stirring
at room temperature with methylene chloride for 1 h and then
extracting as normal. The combined organic layers were
concentrated in vacuo. The resulting yellow oil was first
purified by flash chromatography on silica gel to remove any
byproducts. Elution with ethyl acetate-hexane (75:25) with
the addition of 2% triethylamine afforded a 50:50 mixture of
7a ,b. The two isomers were purified by HPLC using a normal
phase semiprep HPLC column, eluting with hexanes-ethyl
acetate (70:30) with 2% triethylamine at 15 mL/min.
3â-(4′-Ben zylp h en yl)tr op a n e-2â-ca r boxylic Acid Meth -
yl Ester (6b). To a solution of 0.289 g (0.75 mmol) of 9 (RTI-
55) in 7.5 mL of dry degassed THF under nitrogen was added
3.0 mL (1.5 mmol) of 0.5 M benzylzinc chloride in THF,
followed by a catalytic amount of bis(triphenylphosphine)-
palladium(II)chloride. The reaction darkened immediately and
was stirred overnight. To this mixture was added water that
formed a precipitate of zinc salts. The solids were filtered
leaving a biphasic mixture. The product was partially purified
by adding 1 M HCl until acidic and extracting the aqueous
layer with diethyl ether. The remaining aqueous layer was
cooled to 0 °C by adding ice and then basified by the addition
of ammonium hydroxide with stirring until cloudiness per-
sisted. The free base was extracted from the aqueous layer by
first stirring at room temperature with methylene chloride for
1 h and then extracting as normal. The combined organic
layers were concentrated in vacuo. The resulting yellow oil was
purified by flash chromatography on silica gel. Elution with
ethyl acetate-hexane (75:25) with the addition of 2% triethy-
lamine afforded 0.258 g (99%) of 6b. 1H NMR (CDCl3): δ 1.67
(m, 3H), 2.13 (m, 2H), 2.21 (s, 3H), 2.58 (t, 1H, J ) 10.4 Hz),
2.87 (m, 1H), 2.96 (dt, 1H, J ) 5.3, 12.5 Hz), 3.34 (bs, 1H),
3.48 (s, 3H), 3.54 (bs, 1H), 3.91 (s, 2H), 7.07 (d, 2H, J ) 8.0
Hz), 7.16 (m, 5H), 7.24 (d, 2H, 6.8 Hz). 13C NMR (CDCl3): δ
25.6, 26.4, 33.9, 34.5, 41.9, 42.4, 51.5, 53.2, 62.8, 65.8, 126.4,
127.9 (2C), 128.8 (2C), 128.9 (2C), 129.4 (2C), 138.9, 141.2,
141.7, 172.6. The free base was converted to the (D)-tartrate
24
salt; mp 146-148 °C; [R]D -84.2° (c 0.09, MeOH). Anal.
(C27H33NO8‚0.25H2O) C, H, N.
3â-(4′-(1-P h en yl-1-eth en yl)p h en yl)tr op a n e-2â-ca r boxy-
lic Acid Meth yl Ester (6c). To a solution of 0.360 g (0.93
mmol) of 9 (RTI-55) in 9.3 mL of degassed dry THF under
nitrogen was added 3.7 mL (1.87 mmol) of 0.5 M 1-styrenylzinc
chloride in THF, followed by a catalytic amount of bis-
(triphenylphosphine)palladium(II)chloride. The reaction dark-
ened immediately and was stirred overnight. To this mixture
was added water that formed a precipitate of zinc salts. The
solids were filtered leaving a biphasic mixture. The product
was partially purified by adding 1 M HCl until acidic and
extracting the aqueous layer with diethyl ether. The remaining
aqueous layer was cooled to 0 °C by adding ice and then
basified by the addition of ammonium hydroxide with stirring
until cloudiness persisted. The free base was extracted from
the aqueous layer by first stirring at room temperature with
methylene chloride for 1 h and then extracting as normal. The
combined organic layers were concentrated in vacuo. The
resulting yellow oil was purified by flash chromatography on
silica gel. Elution with ethyl acetate-hexane (75:25) with the
(Z)-3â-(4′-(2-P h en yl-1-eth en yl)p h en yl)tr op a n e-2â-ca r -
boxylic Acid Meth yl Ester (7a ). 1H NMR (CDCl3): δ 1.65
(m, 3H), 2.1 (m, 2H), 2.21 (s, 3H), 2.55 (t, 1H, J ) 7.3 Hz),
2.89 (bs, 1H), 2.97 (dt, 1H, J ) 5.2, 12.4 Hz), 3.36 (bs, 1H),
3.49 (s, 3H), 3.52 (bs, 1H), 6.53 (s, 2H), 7.09 (dd, 4H, J ) 7.3,
8.3 Hz), 7.26 (m, 5H). The free base was converted to the
24
hydrochloride salt; mp 101-103 °C; [R]D -136.4° (c 0.05,
MeOH). Anal. (C24H28NClO2‚1.5H2O) C, H, N.
(E)-3â-(4′-(2-P h en yl-1-eth en yl)p h en yl)tr op a n e-2â-ca r -
boxylic Acid Meth yl Ester (7b). 1H NMR (CDCl3): δ 1.60-
1.73 (m, 3H), 2.05-2.23 (m, 2H), 2.23 (s, 3H), 2.61 (dt, 1H, J
) 2.7, 12.3 HZ), 2.92 (m, 1H), 3.02 (dt, 1H, J ) 5.1, 12.6 Hz),
3.38 (bs, 1H), 3.50 (s, 3H), 3.57 (bs, 1H), 7.06 (s, 2H), 7.22-
7.30 (m, 4H), 7.35 (t, 1H, J ) 7.2 Hz), 7.43 (d, 2H, J ) 8.4
Hz), 7.49 (d, 2H, J ) 7.2 Hz). 13C NMR (CDCl3): δ 25.6, 26.3,
34.0, 34.4, 42.4, 51.5, 53.2, 62.7, 65.7, 126.5 (2C), 126.8 (2C),
127.8, 128.0 (2C), 128.3, 129.0 (3C), 135.3, 137.9, 143.1, 172.5.
The free base was converted to the tosylate salt; mp 182-184
°C; [R]D24 -97.6° (c 0.08, MeOH). Anal. (C31H35NO8S‚0.25H2O)
C, H, N.
(E)-3â-(4′-(2-P h en yl-1-eth en yl)p h en yl)tr op a n e-2â-ca r -
boxylic Acid Meth yl Ester (7b). A more direct synthesis of
7b is as follows. To a solution of 0.5 g (1.3 mmol) of 9 (RTI-55)
in 5 mL of degassed toluene were added 0.943 g (1.56 mmol)
of (E)-1,2-bistributylstannylethylene and a catalytic amount
of bis(triphenylphosphine)palladium(II)chloride. The mixture
was heated to reflux. After 45 min, the solution became black
and the reaction was complete. The cooled slurry was filtered
through Celite to remove the palladium. The solution was
concentrated in vacuo forming (E)-stannane 10b.
1
addition of 2% triethylamine afforded 0.288 g (85%) of 6c. H
NMR (CDCl3): δ 1.6-1.76 (m, 3H), 2.0-2.23 (m, 2H), 2.23 (s,
3H), 2.61 (dt, 1H, J ) 2.7, 12.6 Hz), 2.92 (m, 1H), 3.02 (dt,
1H, J ) 5.1, 12.9 Hz), 3.38 (bs, 1H), 3.52 (s, 3H), 3.57 (bs, 1H),
5.38 (s, 1H), 5.44 (s, 1H), 7.21 (d, 2H, J ) 8.7 Hz), 7.25 (d, 2H,
J ) 8.4 Hz), 7.32 (m, 5H). 13C NMR (CDCl3): δ 25.6, 26.3, 34.0,
34.4, 42.4, 51.5, 53.2, 62.7, 64.1, 65.8, 114.2, 127.5 (2C), 128.0,
128.2 (2C), 128.5 (2C), 128.7 (2C), 139.2, 142.1, 143.1, 150.3,
172.6. The free base was converted to the tosylate salt; mp
203-205 °C; [R]D24 -84.7° (c 0.08, MeOH). Anal. (C31H35NO5S)
C, H, N.
(Z)- an d (E)-3â-(4′-(2-P h en yl-1-eth en yl)ph en yl)tr opan e-
2â-ca r boxylic Acid Meth yl Ester (7a ,b). To a solution of
0.584 g (1.5 mmol) of 9 (RTI-55) in 15 mL of degassed toluene
were added 0.804 g (2.3 mmol) of (Z)-1,2-bistrimethylstannyl-
ethylene and a catalytic amount of bis(triphenylphosphine)-
palladium(II)chloride. The mixture was heated to reflux. After
15 min, the solution became black, and the reaction was
complete. The cooled slurry was filtered through Celite to

4036 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Blough et al.
The yellow oil was immediately dissolved in 6.5 mL of dry
methylene chloride, and 0.987 g (3.9 mmol) of iodine was added
to the solution. A dark precipitate formed. The slurry was
stirred for 1 h and then worked up as before. The solution was
concentrated in vacuo to remove excess solvent. The product
was partially purified by adding 1 M HCl until acidic and
extracting the aqueous layer with diethyl ether. The remaining
aqueous layer was cooled to 0 °C by adding ice and then
basified by the addition of ammonium hydroxide with stirring
until cloudiness persisted. The free base was extracted from
the aqueous layer by first stirring at room temperature with
methylene chloride for 1 h and then extracting as normal. The
combined organic layers were concentrated in vacuo. The
resulting yellow oil was purified by flash chromatography on
silica gel. Elution with ethyl acetate-hexane (75:25) with the
addition of 2% triethylamine afforded 0.226 g (42%) of (E)-
iodide 11b, which was used without further purification in the
coupling reaction.
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.
Solvent was removed to afford 2.39 g of yellow oil. Purification
by flash chromatography SiO2 using Et2O/Et3N/hexane (45:5:
50) as eluent gave 1.37 g (72%) of the tropene as a slightly
yellow oil, which solidified upon standing. Recrystallization
from Et2O/hexane gave light yellow crystals; mp 98-100 °C;
[R]D22 -75.6° (c 0.27, CHCl3). 1H NMR (CDCl3): δ 7.78 (m, 3H),
7.60 (s, 1H), 7.45 (m. 2H), 7.25 (m, 1H), 3.91 (m, 1H), 3.42 (s,
3H), 3.38 (m, 1H), 2.83 (m, 1H), 2.49 (s, 3H), 1.99-2.32 (m,
4H), 1.69 (m, 1H). 13C NMR (CDCl3): δ 168.50, 143.63, 138.78,
133.15, 132.66, 130.96, 127.99, 127.68, 127.50, 126.14, 125.95,
125.62, 125.24, 60.42, 57.49, 51.36, 37.57, 36.07, 34.36, 30.28.
Anal. (C20H21NO2) C, H, N. The free base was converted to
the (D)-tartaric acid salt. Recrystallization from 2-propanol/
22
Et2O gave a hygroscopic white powder; mp 48 °C (dec); [R]D
-30.8° (c 0.26, CH3OH). 1H NMR (CD3OD): δ 7.86 (m, 3H),
7.72 (s, 1H), 7.49 (m, 2H), 7.30 (m, 1H), 4.64 (m, 1H), 4.07 (m,
1H), 3.50 (s, 3H), 3.25 (m, 1H), 2.94 (s, 3H), 2.75 (m, 1H), 2.41-
2.60 (m, 3H), 2.12 (m, 1H). Anal. (C24H27NO8‚0.5H2O) C, H,
N.
To a solution of 0.111 g (0.27 mmol) of 11b in 2 mL of dry
degassed THF under nitrogen was added phenylzinc chloride,
made as described above by first reacting 0.299 mL (0.54
mmol) of 1.8 M phenyllithium in THF and 1.08 mL (0.54 mmol)
of 0.5 M zinc chloride in THF, followed by a catalytic amount
of bis(triphenylphosphine)palladium(II)chloride. The reaction
darkened immediately and was stirred overnight. To this
mixture was added water that formed a precipitate of zinc
salts. The solids were filtered leaving a biphasic mixture. The
product was partially purified by adding 1 M HCl until acidic
and extracting the aqueous layer with diethyl ether. The
remaining aqueous layer was cooled to 0 °C by adding ice and
then basified by the addition of ammonium hydroxide with
stirring until cloudiness persisted. The free base was extracted
from the aqueous layer by first stirring at room temperature
with methylene chloride for 1 h and then extracting as normal.
The combined organic layers were concentrated in vacuo. The
resulting yellow oil was first purified by flash chromatography
on silica gel to remove any byproducts. Elution with ethyl
acetate-hexane (75:25) with the addition of 2% triethylamine
afforded 0.048 g (49%) of 7b.
3â(2-Na p h t h yl)t r op a n e-2â-ca r b oxylic Acid Met h yl
Ester (12) an d 3r-(2-Naph th yl)tr opan e-2â-car boxylic Acid
Meth yl Ester (13). The tropene 15 (1.00 g, 3.26 mmol) was
dissolved in 5 mL of anhydrous MeOH under Ar. After it was
cooled to -78 °C, the SmI2 solution (0.1 M in THF, 130.0 mL,
13.0 mmol) was added dropwise via syringe. The mixture was
stirred at -78 °C and monitored by TLC. After 1.0 h, the
reaction was quenched by the dropwise addition of a solution
of TFA (3.0 mL) in Et2O at -78 °C. After it was warmed to 0
°C, water was added. 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
to afford an oil. Purification via flash chromatography using
2.5% EtOH/CHCl3 and Et2O/Et3N/hexane (9:1:30) as eluent
gave the desired 2â,3R and 2â,3â isomers 13 and 12, respec-
tively.
(E)-3â-(4′-(3-P h en yl-1-p r op en yl)p h en yl)tr op a n e-2â-ca r -
boxylic Acid Meth yl Ester (8). To a solution of 0.115 g (0.28
mmol) of the 11b prepared above for 7b in 2 mL of dry
degassed THF under nitrogen was added 1.08 mL (0.56 mmol)
of 0.5 M benzylzinc chloride in THF, followed by a catalytic
amount of bis(triphenylphosphine)palladium(II)chloride. The
reaction darkened immediately and was stirred overnight. To
this mixture was added water that formed a precipitate of zinc
salts. The solids were filtered leaving a biphasic mixture. The
product was partially purified by adding 1 M HCl until acidic
and extracting the aqueous layer with diethyl ether. The
remaining aqueous layer was cooled to 0 °C by adding ice and
then basified by the addition of ammonium hydroxide with
stirring until cloudiness persisted. The free base was extracted
from the aqueous layer by first stirring at room temperature
with methylene chloride for 1 h and then extracting as normal.
The combined organic layers were concentrated in vacuo. The
resulting yellow oil was first purified by flash chromatography
on silica gel to remove any byproducts. Elution with ethyl
acetate-hexane (75:25) with the addition of 2% triethylamine
The tropane 13 was isolated in 19.1% yield as an oil. 1H
NMR (CDCl3): δ 7.76 (m, 3H), 7.66 (m, 1H), 7.33-7.47 (m,
3H), 3.56 (s, 3H), 3.54 (m, 1H), 3.40 (m, 1H), 3.31 (m, 1H),
2.67 (dd, 1H), 2.52 (m, 1H), 2.28 (s, 3H), 2.11-2.25 (m, 2H),
1.48-1.64 (m, 3H). 13C NMR (CDCl3): 175.20, 141.65, 133.42,
132.18, 127.94, 127.68, 127.52, 126.36, 125.88, 125.35, 63.26,
59.66, 56.05, 51.78, 41.11, 38.88, 36.22, 28.84.
The tropane 13 was characterized as its (D)-tartaric acid salt;
1
mp 55 °C (dec); [R]D -60.0° (c 0.28, CH3OH). H NMR (CD3-
OD): δ 7.85 (m, 4H), 7.44-7.56 (m, 3H), 4.19 (m, 1H), 3.97
(m, 1H), 3.67 (s, 3H), 3.62 (m, 1H), 3.47 (m, 1H), 2.84 (s, 3H),
2.67 (m, 1H), 2.31-2.43 (m, 3H), 2.04 (m, 2H). Anal. (C24H29
-
NO8‚0.5H2O) C, H, N. The tropane 12 was isolated in 19.4%
yield as an oil. 1H NMR (CDCl3): δ 7.75 (m, 4H), 7.41 (m, 3H),
3.58 (m, 1H), 3.44 (s, 3H), 3.40 (m, 1H), 3.14 (m, 1H), 3.03 (m,
1H), 2.72 (m, 1H), 2.31 (s, 3H), 2.10-2.29 (m, 2H), 1.65-1.84
(m, 3H). 13C NMR (CDCl3): 172.14, 140.80, 133.37, 127.81,
127.47, 127.33, 125.90, 125.84, 125.69, 125.16, 65.42, 62.33,
52.84, 51.16, 42.04, 34.19, 33.93, 26.00, 25.26. Anal. (C24H29
-
NO8‚0.5H2O) C, H, N.
1
afforded 0.081 g (77%) of 8. H NMR (CDCl3): δ 1.64 (m, 3H),
The tropane 12 was characterized as its (D)-tartaric acid salt;
2.22 (m, 2H), 2.21 (s, 3H), 2.58 (t, 1H, J ) 12.2 Hz), 2.88 (bs,
1H), 2.96 (dd, 1H, J ) 5.9, 12.5 Hz), 3.35 (bs, 1H), 3.47 (s,
3H), 3.49 (m, 3H), 6.28 (dt, 1H, J ) 6.7, 15.7 Hz), 6.40 (d, 1H,
J ) 15.9 Hz), 7.16 (m, 9H). The free base was converted to
1
mp 106 °C (dec); [R]D -85.4° (c 0.26, CH3OH). H NMR (CD3-
OD): δ 7.83 (m, 3H), 7.70 (s, 1H), 7.38-7.49 (m, 3H), 4.18 (m,
1H), 4.11 (m, 1H), 3.75 (m, 1H), 3.30 (m, 1H), 2.96 (s, 3H),
2.95 (m, 1H), 2.26-2.55 (m, 4H), 2.08 (m, 1H). Anal. (C24H29
NO8‚0.5H2O) C, H, N.
-
24
hydrochloride salt; mp 116-118 °C; [R]D -110.5° (c 0.09,
MeOH). Anal. (C25H30NClO2‚2H2O) C, H, N.
Ack n ow led gm en t. This research was supported by
the National Institute on Drug Abuse, Grant Nos.
DA05477 and DA00418.
3-(2′-Na p h t h yl)t r op en e-2-ca r b oxylic Acid Met h yl
Ester (15). To a round bottom flask were added the triflate
14 (2.026 g, 616 mmol). LiCl (0.503 g, 12.0 mmol), Pd-
[P(C6H5)3]4 (0.203 g), Na2CO3 (2.0 M solution in H2O, 6.0 mL,
12.0 mmol), and diethoxymethane (15 mL). The mixture was
stirred vigorously, and 2′-naphthyl boronic acid (1.234 g, 7.18
mmol) was added. After 2 h reflux, the reaction mixture was
filtered through Celite. Et2O and H2O were added, and the
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