Structure-activity relationship comparison of (S)-2β-substituted 3α-(bis[4-fluorophenyl]methoxy)tropanes and (R)-2β-substituted 3β-(3,4-dichlorophenyl)tropanes at the dopamine transporter

Article abstract of DOI:10.1021/jm0300375

Extensive structure-activity relationships at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2β-carboalkoxy-3α-(bis[4-fiuorophenyl]methoxy)tropanes (11a-f, 13-16) and their identically (R)-2β-substituted 3β-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of [³H]dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K_i = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato-(16) (S)-2β-carbophenylethoxy-3α-(bis[4-fluorophenyl] methoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC₅₀ = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.

Full text of DOI:10.1021/jm0300375

2908
J . Med. Chem. 2003, 46, 2908-2916
Str u ctu r e-Activity Rela tion sh ip Com p a r ison of (S)-2â-Su bstitu ted
3r-(Bis[4-flu or op h en yl]m eth oxy)tr op a n es a n d (R)-2â-Su bstitu ted
3â-(3,4-Dich lor op h en yl)tr op a n es a t th e Dop a m in e Tr a n sp or ter
Mu-Fa Zou,† Theresa Kopajtic,‡ J onathan L. Katz,‡ and Amy Hauck Newman*,†
Medicinal Chemistry and Psychobiology Sections, Intramural Research Program, National Institute on Drug Abuse,
National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224
Received J anuary 23, 2003
Extensive structure-activity relationships at the dopamine transporter (DAT) have been
developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent
structural requirements for optimal DAT binding suggest that these tropane-based DAT
inhibitors may not access identical binding domains. To further investigate this hypothesis, a
series of (S)-2â-carboalkoxy-3R-(bis[4-fluorophenyl]methoxy)tropanes (11a -f, 13-16) and their
identically (R)-2â-substituted 3â-(3,4-dichlorophenyl)tropanes (3, 5a -d ) were prepared and
evaluated for binding at the DAT and for inhibition of [3H]dopamine uptake in rat brain. These
studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the
two classes of compounds, bind with high affinity to DAT (Ki ) 5.5-100 nM), albeit with opposite
stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2â-carbophe-
nylethoxy-3R-(bis[4-fluorophenyl]methoxy)tropanes demonstrated a significant decrease in DAT
binding potency (IC50 ) 210 and 537 nM, respectively), suggesting that the DAT does not tolerate
2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes.
In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and
muscarinic receptors were evaluated and compared for compounds 2, 3, 11a -e, and 13.
Together, the binding profiles across these systems demonstrated significant differences between
these two classes of tropane-based ligands, which may be exploited toward the discovery of a
cocaine-abuse pharmacotherapeutic.
Cocaine is a highly addictive central nervous system
stimulant (for recent reviews, see refs 1-3). Although
the identification of mechanism(s) associated with co-
caine addiction remains uncertain, its psychostimulant
and reinforcing effects are associated with its inhibition
of dopamine reuptake into dopaminergic neurons via the
dopamine transporter (DAT).4-7
Extensive structure-activity relationship (SAR) stud-
ies of cocaine analogues at the DAT have led to the
discovery of a potent class of DAT inhibitors wherein
the 3-benzoyl ester was replaced with various aryl ring
systems to give more potent 2-carbomethoxy-3-aryltro-
pane analogues (for a review, see ref 8). The most potent
DAT inhibitors in this class of analogues, as well as
cocaine, must possess a 2-substituent, and the R-
configuration is generally required.3,8 Although the
enantiomeric requirement for an R-2â-substituent is
stringent, a wide variety of chemical moieties with
differing steric and electronic properties are well toler-
ated. Many of these compounds have demonstrated
utility as radioligands and irreversible and fluorescent
probes.9-12
1-055) binds with high affinity to DAT (Ki ) 11.8 nM).13
Meltzer and colleagues synthesized all eight isomers
of 2-carbomethoxy-3R-(bis[4-fluorophenyl]methoxy)tro-
pane and discovered that the S-enantiomer, S-(+)-
difluoropine, demonstrated considerably higher affinity
for the DAT than any of the other seven isomers.14
Numerous 3-aryltropane analogues have been evalu-
ated in animal models of cocaine abuse and with few
exceptions are generally potent psychomotor stimulants
with reinforcing effects that mimic those of cocaine.4,15-17
These behaviors have been attributed primarily to their
interactions at the DAT and subsequent inhibition of
dopamine uptake. Nevertheless, recently there have
been reported exceptions.18
In contrast, the benztropine analogues, with few
exceptions, do not demonstrate cocaine-like behavioral
profiles despite being potent dopamine uptake inhibitors
both in vitro and in vivo.3,19 Because the DAT tolerates
significant modification of the 2-substituent in the
3-aryltropane class of compounds, it was of interest to
determine what 2-substitutions in the benztropine class
would be permitted. Thus, a SAR comparison of a series
of 2-substituted S-(+)-2â-carboalkoxy-3R-(bis[4-fluo-
rophenyl]methoxy)tropanes with the identically substi-
tuted R-(-)-2â-carboalkoxy-3â-(3,4-dichlorophenyl)tro-
panes was undertaken (Figure 1).
In another class of tropane-based DAT ligands, based
on 3R-(diphenylmethoxy)tropane (benztropine), a sub-
stituent in the 2-position is not necessary for high-
affinity DAT binding. For example, compound 2 (AHN
It has been previously demonstrated that the 3â-(3,4-
dichlorophenyl)tropane pharmacophore binds optimally
to the DAT, and thus, this compound (3) was chosen as
the parent ligand for the 3-aryltropane series20,21 from
* To whom correspondence should be addressed. E-mail: anewman@
intra.nida.nih.gov. Phone: 410-550-1455. Fax: 410-550-1621.
† Medicinal Chemistry Section.
‡ Psychobiology Section.
10.1021/jm0300375 This article not subject to U.S. Copyright. Published 2003 by the American Chemical Society
Published on Web 05/31/2003

Comparison of Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2909
previously communicated for compounds 11a -d .22 Con-
version to the carboxylic acid intermediate 9 was
followed by esterification in the appropriate alcohol,
under acidic conditions to give the esters 10a -f. The
final products 11a -f were obtained using a standard
procedure.14 Full experimental details for these com-
pounds are included in the Experimental Section and
were not previously described.
Synthesis of the potential irreversible ligands 15 and
16 is depicted in Scheme 2. Compound 11f was reduced
to amine 13 by catalytic hydrogenation (10% Pd/C). By
use of a modification of procedures previously de-
scribed,24 compound 13 was reacted with ICl to give
intermediate 14, which was first treated with NaNO2
under acidic conditions and then reacted with NaN3 to
give the iodoazido product 15. Compound 13 was
converted to 16 by treatment with CSCl2.
Str u ctu r e-Activity Rela tion sh ip s
Binding affinities of all novel compounds were evalu-
ated in radiolabeled ligand displacement assays for DAT
in rat brain. The methods for the binding assays have
been previously described in detail.25 Inhibition of [3H]-
dopamine uptake in rat synaptosomes was also evalu-
ated using a previously reported procedure.26 The
results of these studies are in Table 1. Most of the
compounds in both series demonstrated high binding
affinity at the DAT, although the S-(+)-2â-carboalkoxy-
3R-[bis(4-difluorophenyl)methoxy]tropane compounds
were consistently and slightly less potent than the
identically substituted 3,4-dichlorophenyltropanes (e.g.,
3, DAT Ki ) 6.30 nM vs 11a , DAT Ki ) 13.4 nM). When
the steric bulk of the 2-position ester in both series was
increased, DAT binding affinities decreased only slightly.
For the S-(+)-2â-carboethoxyphenyl analogue (11e, Ki
) 36.7 nM), nitro substitution at the 4-position of the
terminal phenyl ring resulted in a ∼2.5-fold decrease
in binding affinity to the DAT (11f, Ki ) 97.7 nM).
Whereas reduction of the nitro group to the amine (13,
Ki ) 36.7 nM) resulted in a ∼2.5-fold increase in binding
affinity, the addition of the 3′-iodo substituent (14, Ki
) 42.3 nM) did not appreciably alter binding affinity at
the DAT. However, conversion of the amine to the azide
or isothiocyanate gave rise to dramatic decreases in
DAT binding potencies in the 3R-(bis[4-fluorophenyl]-
methoxy)tropane series (15, IC50 ) 210 nM and 16, IC50
) 537 nM). In contrast, the 4′-azido-substituted 17 (RTI
82), binds with high potency to the DAT (IC50 ) 14.5
nM). Indeed, it is predicted that the 3,4-dichloro-
substituted analogue of 17 would have even higher
binding potency at the DAT. These results suggest that
the DAT tolerates more steric bulk in the 2-position of
the 3,4-dichlorophenyltropanes than is tolerated with
the 3R-(bis[4-fluorophenyl]methoxy)tropanes. In fact,
the small differences in binding affinities of the smaller
2-carboalkoxy analogues (11a -e) compared to those of
the unsubstituted compound 2 may suggest that these
substituents have insignificant interactions at the DAT.
However, when the substituent is sterically bulky and
perhaps electronically unfavorable, DAT binding affini-
ties decrease because of detrimental interactions. Nev-
ertheless, despite its reduced binding potency, com-
pound 15 will be further investigated for wash-resistant
binding and may still be a useful photoaffinity label for
the DAT.
F igu r e 1. Chemical structures of cocaine (1), the parent
compounds 2 and 3, and the target compounds.
which compounds 5a -d were derived. As previously
communicated, an enantioselective synthesis of the
S-(+)-2â-carboalkoxy-3R-(bis[4-fluorophenyl]methoxy)-
tropanes22 was further elaborated upon to give >99%
enantiomeric excess (ee) products (11a -f, 13, 14).
Evaluation of these novel compounds for DAT binding
and inhibition of dopamine uptake (DAUI) was inves-
tigated. Further, how this chemical modification affected
binding profiles at the other monoamine transporters
and muscarinic receptors was also examined. In addi-
tion, in an attempt to prepare novel irreversible ligands
for the DAT, S-2â-carboethoxyphenylisothiocyanato-
and azido-substituted analogues (15, 16) of the 3R-(bis-
[4-fluorophenyl]methoxy)tropane series were also pre-
pared.
Ch em istr y
The R-(-)-2â-carboalkoxy-3â-(3,4-dichlorophenyl)tro-
panes were prepared from 3.12 Deesterification in 6 N
aqueous HCl gave the carboxylic acid intermediate 4,
which was first converted to the acid chloride and then
esterified with the corresponding alcohols to generate
compounds 5a -d .
The enantioselective synthesis of the common
intermediate 8 for the S-(+)-2â-carboalkoxy-3R-[bis(4-
difluorophenyl)methoxy]tropanes (11a -f) was achieved
through the asymmetric deprotonation strategy of Ma-
jewski and Lazny,23 as depicted in Scheme 1 and

2910 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Zou et al.
Sch em e 1a
a
Reagents and conditions: (a) (1) n-BuLi, 12, THF, (2) NCCO2Me, 77%; (b) resolution with D-tartaric acid, 80%; (c) H2 (50 psi), PtO2,
EtOH, 86%; (d) H2O, reflux; (e) ROH, HCl; (g) room temp or heating; (f) 4,4′-difluorobenzhydrol, p-TSA, benzene, reflux, 10.3-47.5% yield
from compound 8.
Sch em e 2a
a
Reagents and conditions: (a) H2 (40 psi), Pd/C (10%), MeOH, 1 h, 70%; (b) ICl, HOAc, 49%; (c) (1) NaNO2, HOAc/H2O, 0 °C, (2) NaN3,
0 °C, 63%; (d) CSCl2, CHCl3/H2O, 0 °C, 81%.
Figure 2 provides a Molcad surface comparison of
compounds 15 and 17 to provide a depiction of these
two molecules in three-dimensional space. On the basis
of their SAR, a large binding pocket on DAT appears to
be available for the 3-aryltropanes but is more limited
for the benztropine analogues. Coupled with opposite

Comparison of Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2911
Ta ble 1. DAT Binding and Dopamine Uptake Inhibition Data for Novel 2-Substituted Tropanes
[3H]WIN 35,428
[3H]DAUI,
IC50 ( SEM (nM)
a,b
b
compd
structure
R
DAT, Ki
( SEM (nM)
3
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
CH3
6.30 ( 0.7
1.4 ( 0.2
1.9 ( 0.2
2.7 ( 0.4
19 ( 2.8
3.2 ( 0.4
NT
5a
5b
5c
5d
CH2CH3
CH(CH3)2
CH2Ph
CH2CH2Ph
CH2CH2Ph-3′-I,4′N3
CH3
CH2CH3
CH(CH3)2
CH2Ph
CH2CH2Ph
CH2CH2Ph-4′NO2
CH2CH2Ph-4′NH2
CH2CH2Ph-3′-I,4′NH2
CH2CH2Ph-3′-I,4′N3
CH2CH2Ph-4′NCS
5.54 ( 0.2
17.9 ( 1.6
34.7 ( 3.1
10.9 ( 0.5
14.5 ( 0.94d,e
13.4 ( 0.9
16.4 ( 2.0
30.3 ( 2.0
48.4 ( 6.1
36.7 ( 4.2
97.7 ( 14
36.7 ( 2.0
42.3 ( 4.0
210 ( 29d
537 ( 37d
285 ( 27
17, RTI 82c
11a
11b
11c
11d
11e
11f
13
14
1.5 ( 0.2f
1.8 ( 0.2f
6.2 ( 0.3f
2.2 ( 0.3f
2.6 ( 018
3.3 ( 0.30
8.0 ( 0.63
NT
NT
NT
236 ( 21
13.8 ( 1.7
15
16
1, cocaine
2, AHN 1-055
11.8 ( 1.3g
a
Each Ki value represents data from at least three independent experiments, each performed in triplicate. Ki values were analyzed by
PRISM. A detailed description of DAT binding and DAUI assay methods have been previously published.25,26 c 17 does not have a 3′-Cl
b
group but is included for comparison. IC50 value. e Data from ref 24. f Data from ref 22. Data from ref 13.
d
g
stereoselectivity requirements at the 2-position, these
results provide further evidence that these two classes
of tropane-based DAT inhibitors bind at different do-
mains on the DAT.
have widely differing SARs at these three proteins, as
with the DAT.
In addition to DAT binding affinities, potency for
inhibiting [3H]dopamine uptake (DAUI) in vitro was
assessed (Table 1). Both series of compounds also
showed high potency in inhibiting [3H]dopamine uptake,
and these IC50 values were generally similar across
identically 2-substituted tropanes. Interestingly, in
general, the 2-carboalkoxy-substituted 3R-(bis[4-fluo-
rophenyl]methoxy)tropanes were more potent in inhib-
iting dopamine uptake than in binding to the trans-
porter (e.g., 11d , Ki ) 48.4 nM and IC50 for DAUI ) 2.2
nM). This is in contrast to the parent compound 2, which
showed similar values for binding affinity to the DAT
(Ki ) 11.8 nM) and potency for inhibition of dopamine
uptake (IC50 ) 13.8 nM). Disparity in potency in various
functional assays compared to binding constants may
be related to assay conditions and might not be reflected
in vivo. However, these differences appear to be related
to compound structure, with the 2-substituted benz-
tropine analogues showing these differences more pro-
foundly than the 3-aryltropanes, which were studied
under identical conditions. Further, the differences
between values for in vitro DAT binding vs DAUI have
not been previously encountered with the benztropine
analogues lacking a 2-position substituent (e.g., 2). The
possibility that they may be reflected in different in vivo
profiles is certainly intriguing and will be investigated
further.
Compounds 11a -e and 13 were evaluated for binding
affinities at the serotonin transporter (SERT), norepi-
nephrine transporter (NET), and muscarinic receptors
and compared to the parent ligands 2 and 3 (Table 2).
In general, none of these analogues demonstrated high
binding affinities to the NET or SERT as did compound
3. Likewise, none of the compounds showed high-affinity
binding to muscarinic receptors, compared to 2, dem-
onstrating that the 2-substituent serves to diminish
muscarinic receptor interactions in this class of
compounds. Thus, good DAT selectivity over SERT,
NET, and muscarinic receptors was observed with the
S-(+)-2â-carboalkoxy-3R-(bis[4-fluorophenyl]methoxy)-
tropanes. In a comparison of compounds 2 and 11a ,
addition of the 2-methyl ester increases binding affinity
at the SERT and NET by 5- and 2-fold, respectively.
However, this addition significantly reduces muscarinic
receptor binding by 12-fold. Increasing steric bulk
further decreases binding affinities at the SERT, NET,
and muscarinic receptors, with compound 11c demon-
strating the highest overall DAT selectivity (i.e., SERT/
DAT ) 400, NET/DAT ) 20, M1/DAT ) 90). Interest-
ingly, when the 2-substituent gets very large, as in
compounds 11e and 13, muscarinic receptor binding
begins to improve. In contrast, compound 3 binds with
high affinities to the SERT and NET but with very low
affinity to muscarinic receptors. These data clearly
demonstrate that these classes of tropane-based ligands
In summary, identically 2â-carboalkoxy-substituted
R-(-)-3â-(3,4-dichlorophenyl)tropanes and S-(+)-3R-(bis-
[4-fluorophenyl]methoxy)tropanes were synthesized.

2912 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Zou et al.
F igu r e 2. Molcad surface analyses of 15 and 17 demonstrate steric bulk in the 2-position of these molecules. Compound 17 is
well tolerated at the DAT (IC50 ) 14.5 nM), whereas 15 binds with significantly lower potency (IC50 ) 210 nM).
Ta ble 2. Binding Results at the SERT, NET, and Muscarinic
M1 Receptors
and to compare these to cocaine and the 3-aryltropanes
in vivo. Currently, behavioral evaluation of 11a -c in
[3H]citalopram [3H]nisoxetine [3H]pirenzepine
animal models of cocaine abuse is underway. Exploring
the behavioral outcomes of structurally similar but
distinct DAT inhibitors that exhibit significantly dif-
ferent binding profiles at SERT and NET may provide
clues toward an optimal behavioral profile for potential
cocaine-abuse medication.
SERT
NET
M1
a
a
a
Ki ( SEM
Ki ( SEM
Ki ( SEM
compd
(+)-11a
(nM)
(nM)
(nM)
690 ( 58b
269 ( 39b
629 ( 31b
133 ( 4.2b
1890 ( 130b
2680 ( 140b
4380 ( 530b
354 ( 52
(+)-11b
(+)-11c
(+)-11d
(+)-11e
13
1850 ( 270b
12000 ( 1280b 642 ( 13b
2040 ( 300b
3160 ( 461
1500 ( 210
2230 ( 200b
1030 ( 85
1340 ( 120
610(81b
Exp er im en ta l Meth od s
263 ( 5.6
2, AHN 1-055 3260 (110b
11.6 ( 0.9b
3140 ( 260
All melting points were determined on a Thomas-Hoover
1
melting point apparatus and are uncorrected. The H and 13C
3
1.46 ( 0.2
15.8 ( 1.6
NMR spectra were recorded on a Bruker (Billerica, MA) AC-
300 instrument. Samples were dissolved in an appropriate
deuterated solvent (CDCl3 or CD3OD). Proton and carbon
chemical shifts are reported as parts per million (δ) relative
to tetramethylsilane (Me4Si, 0.00 ppm), which was used as an
internal standard. To maximize the signal-to-noise ratio, all
spectra for the 1H NMR analysis of the enantiomeric excess
value (% ee) were recorded on samples (0.10-0.15 M) in the
presence of ca. 15 mg of S-(+)-2,2,2-trifluoro-1-(9-antranyl)-
ethanol [S-(+)-TFAE]. The enantiomeric analyses were con-
ducted on the chiral HPLC column “Klassix Chiral-A”, 250 mm
× 4.6 mm i.d., 10 µm (flow rate of 1 mL/min). Mass spectra
were recorded on a Hewlett-Packard (Palo Alto, CA) 5973
mass-selective ion detector in the electron-impact mode with
sample introduction via an HP-6890 series gas chromatograph
fitted with an HP-1 (cross-linked methyl silicone gum) 25 m
× 0.2 mm i.d., 50 µm film thickness. Ultrapure grade helium
was used as the carrier gas at a flow rate of 1.2 mL/min. The
injection port and transfer line temperatures were 250 and
280 °C, respectively. The initial oven temperature was 100 °C,
held for 3.0 min, programmed to 295 °C at 15.0 °C/min, and
maintained at 295 °C for 10-23 min. Infrared spectra were
recorded as a neat film on KBr plates with a Perkin-Elmer
Spectrum RX I FT-IR system. Microanalyses were performed
by Atlantic Microlab, Inc. (Norcross, GA) and agree within
(0.4% of the calculated values. All flash column chromatog-
a
Each Ki value represents data from at least three independent
experiments, each performed in triplicate. Ki values were analyzed
by PRISM. A detailed description of SERT, NET, and muscarinic
receptor binding assay methods have been previously published.25
b
Data from ref 22.
Binding evaluation revealed that both series of com-
pounds were highly potent DAT ligands that inhibited
dopamine uptake with high and equivalent potencies.
The exceptions were the potential irreversible ligands
15 and 16 that, unlike 17, were significantly less potent
than the other analogues in this series. Comparison of
the SAR suggests that the two series of ligands likely
bind at different domains on the DAT protein. These
differences may be exploited toward developing tools
with which to map the topology of the DAT. Signifi-
cantly different binding profiles at SERT, NET, and
muscarinic receptors suggest that these tropane-based
molecules do not interact at these proteins in a similar
manner either. Furthermore, it is of considerable inter-
est to further investigate the differences in dopamine
uptake inhibition between the unsubstituted benz-
tropine analogues and their 2-substituted counterparts

Comparison of Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2913
raphy was performed using the flash-grade silica gel (Aldrich,
230-400 mesh, 60A). All chemicals and reagents were pur-
chased from Aldrich Chemical Co. or Lancaster Synthesis, Inc.
unless otherwise indicated and used without further purifica-
tion.
to -78 °C, a solution of tropinone (5.06 g, 36.3 mmol) in THF
(36 mL) was added dropwise and the resulting mixture was
stirred for 2.5 h at -78 °C. Methyl cyanoformate (4.32 mL,
54.5 mmol) was then added quickly to the solution, and the
mixture was stirred at -78 °C for 30 min followed by
quenching with AgNO3 (6.5 g, 36 mmol) in THF (36 mL), H2O
(9 mL), and HOAc (9 mL). Immediately after warming to room
temperature, the mixture was treated with NH4OH (to dissolve
the Ag salts), diluted with H2O, and extracted with CHCl3 (3
× 100 mL). The combined extracts were dried over anhydrous
MgSO4, the solvents were removed in vacuo, and the residue
was purified by flash column chromatography (hexanes/EtOAc/
Et3N, 3:1:0.5, followed by CHCl3/MeOH/NH4OH, 95:5:1) to give
5.5 g (77%) of 7 as a white solid: 92% ee by 1H NMR with
S-(+)-TFAE. Mp 102-104 °C. D-Tartaric acid (15 g, 10 mmol)
was added to the hot solution of 7 (10 g, 5.08 mmol) in EtOH
(150 mL). EtOH was removed in vacuo after all the tartaric
acid was dissolved. The residue was recrystallized once from
a 10:1 acetone/H2O mixture and then from MeOH to afford
20.7 g of (-)-2R-carbomethoxytropinone bitartrate as a colorless
crystalline solid. The salt was dissolved in saturated Na2CO3
(50 mL), and the free base was extracted with CHCl3 (3 × 25
mL). The dried (K2CO3) extracts were concentrated to afford
Gen er a l P r oced u r e for th e P r ep a r a tion of R-(-)-2â-
Car boalkoxy-3â-(3,4-dich lor oph en yl)tr opan es 5a -d fr om
3. Compound 3 (330 mg, 1 mmol)12 was dissolved in aqueous
HCl (6 N, 10 mL), and the mixture was heated to gentle reflux
for 6 h. H2O was then removed, and the residue was further
dried under vacuum to give 4 as a solid that was used without
further purification. To compound 4, 5 mL of POCl3 was added,
and the mixture was stirred overnight at room temperature
under an argon atmosphere. Excess POCl3 was removed in
vacuo. The residue was dissolved in dry CH2Cl2 (10 mL) and
cooled to 0 °C. The corresponding alcohol (4 mmol, 4 equiv)
was added followed by dropwise addition of Et3N (0.7 mL, 5
mmol). The solution was warmed to room temperature and
stirred for 3 h. H2O (10 mL) was added, the mixture was
separated, and the aqueous layer was extracted with CHCl3
(3 × 10 mL). The combined organic layer was dried (K2CO3)
and concentrated. The residue was purified by flash column
chromatography to give the pure products.
1
8.03 g (80%) of 7 as a white solid: >99% ee by H NMR with
R-(-)-2â-Ca r boeth oxy-3â-(3,4-d ich lor op h en yl)tr op a n e
(5a ). Compound 5a was prepared and isolated as a white solid
S-(+)-TFAE. Mp 107-108 °C; lit.28 sublimed mp 108.6-109.6
°C; [R]27D -22.8° (c 1.0, MeOH); lit.28 [R]20D -18.3° (c 1, MeOH).
in 81% yield. Mp 70-71.5 °C; [R]25 -26.8° (c 1.0, CH3OH);
D
IR 1735, 1180 (br) cm-1; H NMR (CDCl3) δ 1.11 (3H, t, J )
1
S-(+)-Allop seu d oecgon in e Meth yl Ester (8). Compound
7 (1.97 g, 10 mmol) was dissolved in absolute EtOH (80 mL)
and reduced by hydrogenation over PtO2 catalyst (80 mg) at
50 psi for 4 days. The catalyst was removed using suction
filtration through Celite, and the solvent was removed under
vacuum. The residue was purified by column chromatography
(CHCl3/MeOH/NH4OH, 90:10:1) to afford 1.71 g (86%) of 8 as
7.1 Hz, OCH2CH3), 1.53-1.73 (3H, m), 2.05-2.25 (2H, m), 2.22
(3H, s, NCH3), 2.50 (1H, m), 2.82-2.98 (2H, m, H-2, H-3), 3.35
(1H, m, H-5), 3.59 (1H, m, H-1), 3.83-3.96 (1H, m, OCH2),
4.00-4.11 (1H, m, OCH2), 7.11 (1H, m, Ar-H), 7.31 (2H, m,
Ar-H) ppm; 13C NMR (CDCl3) δ 14.5, 25.6, 26.2, 33.6, 34.4,
42.3, 52.9, 60.2, 62.4, 65.7, 127.1, 129.9, 130.1, 132.2, 144.2,
171.7 ppm; EIMS (m/z) 327 (M+). Anal. (C17H21NCl2O2‚2HCl)
C, H, N.
a colorless solid. Mp 74-76 °C; lit.29 mp 79-80 °C; [R]24
D
+35.9° (c 1, CHCl3); lit.29 [R]20 +37.7° (c 1, CHCl3); H NMR
1
D
(CDCl3) δ 1.81-2.10 (6H, m), 2.32 (3H, s, NCH3), 2.91 (1H, t,
J ) 3.6 Hz, H-2), 3.11 (1H, m, H-5), 3.35 (1H, m, H-1), 3.46
(1H, br, OH), 3.75 (3H, s, OCH3), 4.27 (1H, m, H-3) ppm; 13C
NMR (CDCl3) δ 24.7, 26.1, 37.8, 40.4, 50.5, 52.2, 60.2, 62.1,
65.0, 174.5 ppm; EIMS (m/z) 199 (M+).
S-(+)-Alloecgon in e (9). Compound 8 (498 mg, 2.5 mmol)
was suspended in H2O (20 mL), and the mixture was stirred
at reflux for 18 h. H2O was removed in vacuo, and the residue
was further dried to give 9 as a colorless solid. The crude
product was used in the next step without further purification.
R-(-)-2â-Ca r bo-2-p r op oxy-3â-(3,4-d ich lor op h en yl)tr o-
p a n e (5b). Compound 5b was prepared and isolated as a white
solid in 79% yield. Mp 88-90 °C; [R]24 -24.6° (c 1.0, CH3-
D
OH); IR 1727, 1185 (br) cm-1; 1H NMR (CDCl3) δ 1.09 (6H, d,
J ) 6.2 Hz, CH(CH3)2), 1.53-1.73 (3H, m), 2.05-2.25 (2H, m),
2.21 (3H, s, NCH3), 2.51 (1H, m), 2.81 (1H, m, H-3), 2.90 (1H,
m, H-2), 3.34 (1H, m, H-5), 3.58 (1H, m, H-1), 4.91 (1H, m,
OCH), 7.79 (1H, m, Ar-H), 7.30-7.36 (2H, m, Ar-H) ppm;
13C NMR (CDCl3) δ 22.0, 22.2, 25.6, 26.1, 42.3, 52.9, 62.4, 65.7,
67.3, 127.1, 129.8, 130.1, 132.2, 144.4, 171.2 ppm. Anal.
(C18H23NCl2O2‚HCl‚0.5H2O) C, H, N.
S-(+)-Alloecgon in e Meth yl Ester (10a ). Compound 9 was
dissolved in MeOH (15 mL) and acidified with HCl gas for 10
min at 0 °C. The reaction mixture was stirred at room
temperature overnight. MeOH was removed in vacuo, and the
residue was dissolved in H2O (20 mL), neutralized with NH4-
OH to pH 9, and extracted with CHCl3 (3 × 15 mL). The
combined extract was dried (K2CO3) and concentrated to
dryness. The residue was purified by flash column chroma-
tography (CHCl3/MeOH/NH4OH, 95:5:1) to afford 10a (293 mg,
R-(-)-2â-Car boben zoxy-3â-(3,4-dich lor oph en yl)tr opan e
(5c). Compound 5c was prepared and isolated as a colorless
oil in 72% yield. [R]24 -23.4° (c 1.02, CH3OH); IR 1744, 1170
D
(br) cm-1
;
1H NMR (CDCl3) δ 1.53-1.73 (3H, m), 2.05-2.25
(2H, m), 2.19 (3H, s, NCH3), 2.52 (1H, m), 2.87-2.98 (2H, m,
H-2, H-3), 3.36 (1H, m, H-5), 3.59 (1H, m, H-1), 4.86 (1H, d, J
) 12.4 Hz, OCH2Ph), 5.10 (1H, d, J ) 12.4 Hz, OCH2Ph), 7.07
(1H, m, Ar-H), 7.17 (2H, m, Ar-H), 7.25-7.36 (5H, m, Ar-H)
ppm; 13C NMR (CDCl3) δ 25.6, 26.2, 33.6, 34.3, 42.6, 46.6, 53.0,
62.5, 65.6, 66.1, 127.1, 128.3, 128.8, 129.8, 130.2, 132.3, 136.5,
144.0, 171.5 ppm. Anal. (C22H23NCl2O2‚HCl‚1.5H2O) C, H, N.
59%) as a light-brown solid. Mp. 74-76 °C; lit.21 mp 76.5-
1
77.5 °C; [R]24 +3.0° (c 1.0, MeOH); IR 3244, 1749 cm-1; H
D
NMR (CDCl3) δ 1.55-2.20 (6H, m), 2.18 (3H, s, NCH3), 2.62
(1H, m, H-2), 3.08 (1H, br, H-5), 3.57 (1H, m, H-1), 3.71 (3H,
s, OCH3), 4.39 (1H, m, H-3) ppm; EIMS (m/z) 199 (M+).
R-(-)-2â-Ca r bop h en yleth oxy-3â-(3,4-d ich lor op h en yl)-
tr op a n e (5d ). Compound 5d was prepared and isolated as a
white solid in 74% yield. Mp 87-89 °C; [R]24 -24.1° (c 0.85,
S-(+)-Alloecgon in e Eth yl Ester (10b). Compound 10b
was prepared by dissolving 9 in EtOH and acidifying with HCl
D
CH3OH); IR 1734, 1166 (br) cm-1; H NMR (CDCl3) δ 1.50-
1
gas, as described for 10a , giving an oil in 62% yield. [R]26
1.70 (3H, m), 2.00-2.23 (2H, m), 2.11 (3H, s, NCH3), 2.46 (1H,
m), 2.79-2.97 (4H, m, CH2Ph, H-2, H-3), 3.32 (1H, m, H-5),
3.47 (1H, m, H-1), 4.04-4.29 (2H, m, OCH2), 7.07 (1H, m, Ar-
H), 7.10-7.32 (7H, m, 2 Ar-H) ppm; 13C NMR (CDCl3) δ 25.6,
26.2, 33.6, 34.2, 35.3, 42.2, 52.9, 62.5, 64.7, 65.6, 126.8, 127.1,
128.8, 129.2, 129.9, 130.2, 132.3, 138.4, 144.1, 171.6 ppm. Anal.
(C23H25NCl2O2) C, H, N.
D
1
+4.0° (c 1.0, MeOH); H NMR (CDCl3) δ 1.22 (3H, t, J ) 7.0
Hz, CH3), 1.60-2.20 (6H, m), 2.18 (3H, s, NCH3), 2.61 (1H, m,
H-2), 3.10 (1H, m, H-5), 3.58 (1H, m, H-1), 4.07-4.25 (2H, m,
OCH2), 4.34 (1H, d, J ) 5.2 Hz, H-3) ppm; EIMS (m/z) 213
(M+).
S-(+)-Alloecgon in e Isop r op yl Ester (10c). Compound
10c was prepared by dissolving 9 in 2-propanol and acidifying
(-)-2r-Ca r bom eth oxytr op in on e (7). n-BuLi (10 M in
hexane, 4.36 mL, 43.6 mmol) was added dropwise to a solution
of chiral amine 1227 (11.95 g, 43.6 mmol) in dry THF (120 mL)
at 0 °C, and the mixture was stirred for 45 min. LiCl (0.5 M
in THF, 36 mL, 18 mmol) was added, and the solution was
stirred for an additional 15 min. After the mixture was cooled
with HCl gas, as described for 10a , giving an oil in 53% yield.
1
[R]25 +1.2° (c 1.0, MeOH); IR 3506 (br), 1728 cm-1; H NMR
D
(CDCl3) δ 1.22 (3H, d, J ) 4 Hz, CH3), 1.25 (3H, d, J ) 4 Hz,
CH3), 1.57-2.26 (6H, m), 2.18 (3H, s, NCH3), 2.57 (1H, m, H-2),
3.10 (1H, br, H-5), 3.56 (1H, m, H-1), 4.36 (1H, d, J ) 5.1 Hz,

2914 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Zou et al.
H-3), 5.07 (1H, m, OCH) ppm; 13C NMR (CDCl3) δ 21.7, 24.5,
25.3, 39.2, 41.6, 54.2, 60.7, 63.0, 64.8, 67.3, 172.1 ppm; EIMS
(m/z) 227 (M+).
(c 1.0, MeOH); analytic HPLC (Klassix Chiral-A column)
eluting with hexane/2-PrOH/triethylamine (100:1:1) tR ) 6.6
1
min, >99% ee; IR 1726, 1605 cm-1; H NMR (CDCl3) δ 1.22
(3H, t, J ) 7.0 Hz), CH2CH3), 1.70-2.10 (6H, m), 2.18 (3H, s,
NCH3), 2.68 (1H, s, H-2), 3.08 (1H, m, H-5), 3.58 (1H, m, H-1),
3.98 (1H, d, J ) 5.2 Hz, H-3), 4.0-4.2 (2H, m, OCH2), 5.34
(1H, s, OCHPh2), 6.95-7.05 (4H, m, Ar-H), 7.20-7.30 (4H,
m, Ar-H) ppm; 13C NMR (CDCl3) δ 14.2, 24.6, 25.2, 36.2, 41.8,
60.4, 61.0, 63.2, 70.2, 80.3, 115.2, 115.4, 128.4, 138.4, 160.5,
163.7, 172.5 ppm; EIMS (m/z) 415(M+). Anal. (C24H27NF2O3)
C, H, N.
S-(+)-Alloecgon in e Ben zyl Ester (10d ). Compound 10d
was prepared by suspending 9 in benzyl alcohol and acidifying
with HCl gas, as described for 10a . The reaction mixture was
stirred at 50 °C (oil-bath temperature) overnight. The benzyl
alcohol was removed through a short silica gel column, and
the residue was dissolved in H2O (20 mL), neutralized with
NH4OH to pH 9, and extracted with CHCl3 (3 × 15 mL). The
combined extract was dried (K2CO3) and concentrated to
dryness. The residue was purified by column chromatography
S -(+)-2â-Ca r b o-2-p r op oxy-3r-(b is[4-flu or op h e n yl]-
m eth oxy)tr op a n e (11c). Compound 11c was prepared from
(CHCl3/MeOH/NH4OH, 95:5:1) to afford 10d (340 mg, 49.5%)
as an oil. [R]25 +5.8° (c 1.0, MeOH); IR 3394, 1733 cm-1; H
10c as described for 11a in 78% yield. [R]26 +20.2° (c 1.03,
1
D
D
NMR (CDCl3) δ 1.60-2.17 (6H, m), 2.17 (3H, s, NCH3), 2.68
(1H, m, H-2), 3.10 (1H, m, H-5), 3.61 (1H, m, H-1), 4.41 (1H,
d, J ) 5.2 Hz, H-3), 5.10 (1H, d, J ) 12.5 Hz, OCH2), 5.22
(1H, d, J ) 12.5 Hz, OCH2), 7.26-7.40 (5H, m, Ar-H) ppm;
EIMS m/z 275 (M+).
MeOH); analytic HPLC (Klassix Chiral-A column) eluting with
hexane/2-PrOH/triethylamine (100:1.5:1) tR ) 7.4 min, >99%
1
ee; IR 1726, 1603 cm-1; H NMR (CDCl3) δ 1.21 (3H, d, J )
5.8 Hz, CHCH3), 1.23 (3H, d, J ) 5.6 Hz, CHCH3), 1.75-2.17
(6H, m), 2.20 (3H, s, NCH3), 2.66 (1H, m), 3.10 (1H, m), 3.57
(1H, m), 3.98 (1H, d, J ) 5.1 Hz), 5.06 (1H, m, OCH(CH3)2),
5.36 (1H, s, OCHPh2), 6.97-7.04 (4H, m, Ar-H), 7.24-7.31
(4H, m, Ar-H) ppm; 13C NMR (CDCl3) δ 22.2, 25.0, 25.6, 36.5,
42.1, 52.3, 61.4, 63.6, 67.9, 70.6, 80.7, 115.5, 115.8, 128.8, 172.3
ppm; EIMS (m/z) 429 (M+). Anal. (C25H29NF2O3) C, H, N.
S-(+)-Alloecgon in e P h en yleth yl Ester (10e). Compound
10e was prepared by suspending 9 in phenylethyl alcohol and
acidifying with HCl gas, as described for 10d , giving an oil in
21.5% yield. [R]25 +6.3° (c 1.0, CH3OH); IR 1729 cm-1 1H
;
D
NMR (CDCl3) δ 1.5-2.2 (6H, m), 2.10 (3H, s, NCH3), 2.60 (1H,
m, H-2), 2.96 (2H, t, J ) 6.9 Hz, CH2Ph), 3.08 (1H, m, H-5),
3.49 (1H, m, H-1), 4.27-4.41 (3H, m, OCH2, H-3), 7.18-7.31
(5H, m, Ar-H) ppm; 13C NMR (CDCl3) δ 25.0, 25.8, 35.4, 39.7,
42.0, 54.7, 61.2, 63.5, 65.4, 126.9, 128.8, 129.3, 138.4, 173.1
ppm; EIMS (m/z) 289 (M+).
S-(+)-2â-Car boben zoxy-3r-(bis[4-flu or oph en yl]m eth ox-
y)tr op a n e (11d ). Compound 11d was prepared from 10d as
described for 11a in 74.5% yield. [R]26D +12.6° (c 1.05, MeOH);
IR 1733, 1605 cm-1 1H NMR (CDCl3) δ 1.75-2.17 (6H, m),
;
2.17 (3H, s, NCH3), 2.75 (1H, m, H-2), 3.09 (1H, m, H-5), 3.60
(1H, m, H-1), 4.02 (1H, d, J ) 4.8 Hz, H-3), 5.03 (1H, d, J )
12.5 Hz, OCH2), 5.19 (1H, d, J ) 12.5 Hz, OCH2), 5.34 (1H, s,
OCHPh2), 6.93-7.04 (4H, m, Ar-H), 7.21-7.39 (9H, m, Ar-
H) ppm; 13C NMR (CDCl3) δ 25.0, 25.6, 36.6, 42.1, 52.3, 61.4,
63.5, 66.6, 70.5, 80.7, 115.5, 115.8, 128.4, 129.0, 136.5, 138.6,
S-(+)-Alloecgon in e (4-Nit r op h en yl)et h yl E st er (10f).
4-Nitrophenylethyl alcohol (50 g) was melted by heating and
acidified with HCl gas for 10 min. The solution was cooled to
60 °C (oil-bath temperature). To the solution was added 9. The
reaction mixture was stirred at that temperature overnight.
The 4-nitrophenylethyl alcohol was removed through a short
silica gel column, and the residue was dissolved in H2O (20
mL), neutralized with NH4OH to pH 9, and extracted with
CHCl3 (3 × 15 mL). The combined extract was dried (K2CO3)
and concentrated to dryness. The residue was purified by
column chromatography (CHCl3/MeOH/NH4OH, 95:5:1) to
160.8, 164.1, 172.6 ppm; EIMS (m/z) 477 (M+). Anal. (C29H29
-
NF2O3) C, H, N.
S-(+)-2â-Ca r bop h en yleth oxy-3r-(bis[4-flu or op h en yl]-
m eth oxy)tr op a n e (11e). Compound 11e was prepared from
10e as described for 11a in 70% yield. [R]25 +5.7° (c 1, CH3-
D
OH); IR 1731, 1506 cm-1; 1H NMR (CDCl3) δ 1.6-2.1 (6H, m),
2.09 (3H, s, NCH3), 2.67 (1H, m, H-2), 2.91 (2H, t, J ) 6.8 Hz,
CH2Ph), 3.06 (1H, m. H-5), 3.49 (1H, m, H-1), 3.95 (1H, d, J )
4.9 Hz, H-3), 4.21-4.37 (2H, m, OCH2), 5.31(1H, s, OCHPh2),
afford 10f (113 mg, 13.5%) as a dark oil. [R]24 +7.2° (c 1.05,
D
MeOH); IR 1730 cm-1; 1H NMR (CDCl3) δ 1.60-2.18 (6H, m),
2.08 (3H, s, NCH3), 2.61 (1H, m, H-2), 3.03-3.15 (3H, m, H-5,
CH2Ph), 3.42 (1H, m, H-1), 4.30-4.44 (3H, m, H-3, OCH2), 7.42
(2H, d, J ) 8.6 Hz, Ar-H), 8.18 (2H, d, J ) 8.6 Hz, Ar-H)
ppm.
6.94-7.00 (4H, m, Ar-H), 7.13-7.30 (9H, m, Ar-H) ppm; 13
C
NMR (CDCl3) δ 25.0, 25.6, 35.4, 36.5, 42.0, 61.3, 63.5, 65.4,
70.6, 80.7, 115.5, 115.8, 126.9, 128.8, 129.2, 138.4, 138.7, 160.8,
164.1, 172.8 ppm; EIMS (m/z) 491 (M+). Anal. (C30H31NF2O3)
C, H, N.
S-(+)-2â-Car bom eth oxy-3r-(bis[4-flu or oph en yl]m eth ox-
y)tr op a n e (11a ). Compound 10a (200 mg, 1 mmol), 4,4′-
difluorobenzhydrol (440 mg, 2 mmol), p-toluenesulfonic acid
monohydrate (285 mg, 1.5 mmol), and benzene (12 mL) were
placed in a 50 mL round-bottom flask fitted with a Dean-
Stark trap and condenser. The reaction mixture was heated
at reflux for 18 h. Additional 4,4′-difluorobenzhydrol (220 mg,
1 mmol) and p-toluenesulfonic acid monohydrate (24 mg, 0.13
mmol) were added, and the reaction mixture was heated at
reflux for another 6 h. The solvent was removed in vacuo, and
the residue was dissolved in H2O (30 mL), neutralized with
NH4OH to pH 9, and extracted with CHCl3 (3 × 15 mL). The
extracts were combined, dried (K2CO3), and concentrated to
dryness. The residue was purified by column chromatography
(CHCl3/MeOH/NH4OH, 98:2:1) to afford 290 mg (72%) of 11a
as a white solid. Mp: 126.5-127.5 °C; lit.21 mp 132-133 °C;
S-(+)-2â-Ca r b o(4-n it r op h en yl)et h oxy-3r-(b is[4-flu o-
r op h en yl]m eth oxy)tr op a n e (11f). Compound 11f was pre-
pared from 10f as described for 11a in 76% yield as a dark
1
oil. [R]26 +12.5° (c 1, CH3OH); IR 1733, 1507 cm-1; H NMR
D
(CDCl3) δ 1.62-2.12 (6H, m), 2.07 (3H, s, NCH3), 2.68 (1H, m,
H-2), 2.95-3.10 (3H, m, H-5, CH2Ph), 3.45 (1H, m, H-1), 3.93
(1H, d J ) 4.9 Hz, H-3), 4.25-4.42 (2H, m, OCH2), 5.31 (1H,
s, OCHPh2), 6.92-7.03 (4H, m, Ar-H), 7.20-7.28 (4H, m, Ar-
H), 7.36 (2H, d, J ) 8.6 Hz, Ar-H), 8.15 (2H, d, J ) 8.6 Hz,
Ar-H) ppm; 13C NMR (CDCl3) δ 24.5, 25.2, 34.9, 36.0, 41.8,
51.9, 61.0, 63.3, 63.9, 70.0, 80.4, 115.2, 115.5, 123.7, 128.3,
129.8, 138.3, 145.9, 146.8, 160.4, 163.7, 172.3 ppm. Anal.
(C30H30N2F2O5) C, H, N.
S-(+)-2â-Ca r b o(4-a m in op h en yl)et h oxy-3r-(b is[4-flu o-
r op h en yl]m eth oxy)tr op a n e (13). Compound 11f (233 mg,
0.43 mmol) was dissolved in a mixture of CH3OH (5 mL) and
EtOAc (5 mL) and reduced by hydrogenation over 10% Pd/C
catalyst (30 mg) at 40 psi for 30 min. The catalyst was removed
using suction filtration through Celite, and the solvents were
removed under vacuum. The residue was purified by flash
column chromatography (CHCl3/MeOH/NH4OH, 95:5:1) to
21
[R]26 +19.6° (c 1.0, MeOH); lit. [R]21 +21.6° (c 1, MeOH);
D
D
analytic HPLC (Klassix Chiral-A column) eluting with hexane/
2-PrOH/triethylamine (97.5:2.5:0.5) tR ) 9.27 min, >99% ee;
IR 1730, 1605 cm-1 1H NMR (CDCl3) δ 1.65-2.17 (6H, m),
;
2.17 (3H, s, NCH3), 2.72 (1H, m, H-2), 3.09 (1H, m, H-5), 3.56
(1H, m, H-1), 3.68 (3H, s, OCH3), 3.96 (1H, d, J ) 4.8 Hz, H-3),
5.35 (s, 1H, OCHPh2), 6.74-7.05 (4H, m, Ar-H), 7.20-7.32
(4H, m, Ar-H) ppm; EIMS (m/z) 401 (M+). Anal. (C23H25NF2O3)
C, H, N.
afford 13 (154 mg, 70%) as a gum. [R]25 +4.0° (c 1, CHCl3);
D
IR 3371, 1725, 1507 cm-1; 1H NMR (CDCl3) δ 1.60-1.78 (1H,
m), 1.90-2.12 (5H, m), 2.12 (3H, s, NCH3), 2.68 (1H, m, H-2),
2.80 (2H, t, J ) 7.0 Hz, CH2Ph), 3.06 (1H, m, H-5), 3.52 (1H,
m, H-1), 3.58 (2H, br, NH2), 3.96 (1H, d, J ) 4.9 Hz, H-3),
S-(+)-2â-Ca r boeth oxy-3r-(bis[4-flu or op h en yl]m eth ox-
y)tr op a n e (11b). Compound 11b was prepared from 10b as
described for 11a in 76.5% yield. Mp: 60-61 °C; [R]26D +20.5°

Comparison of Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2915
4.10-4.30 (2H, m, OCH2), 5.32 (1H, s, OCHPh2), 6.61 (2H, d,
J ) 8.4 Hz, Ar-H), 6.92-7.05 (6H, m, Ar-H), 7.18-7.30 (4H,
m, Ar-H) ppm; 13C NMR (CDCl3) δ 24.6, 25.2, 34.2, 36.2, 41.7,
51.9, 61.0, 63.1, 65.4, 70.2, 80.3, 115.4, 115.5, 127.8, 128.3,
129.8, 138.3, 138.4, 144.8, 160.4, 163.7, 172.5 ppm; EIMS (m/
z) 506 (M+). Anal. (C30H32N2F2O3) C, H, N.
Intramural Research Program. The authors acknowl-
edge Dr. S. Kulkarni for providing molecular modeling
and for reading an earlier version of this manuscript
and Ms. J . Cao for expert technical assistance.
Refer en ces
S-(+)-2â-Ca r bo(3-iod o-4-a m in op h en yl)eth oxy-3r-(bis-
[4-flu or op h en yl]m eth oxy)tr op a n e (14). Compound 13 (100
mg, 0.2 mmol) was dissolved in glacial HOAc (5 mL). To the
solution was added extremely slowly ICl (36 mg, 0.22 mmol)
in glacial HOAc (2 mL) over 2 h. The solvent was removed
under vacuum. The residue was dissolved in H2O (10 mL) and
neutralized with aqueous NaHCO3 solution to pH 9. The
aqueous solution was extracted with CHCl3 (3 × 5 mL). The
combined organic layers were dried (K2CO3) and concentrated.
The residue was purified by column chromatography (CHCl3/
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MeOH/NH4OH, 95:5:1) to give 14 (62 mg, 49%) as an oil. [R]24
D
+3.5° (c 1.5, CHCl3); IR 3369 (br), 1725, 1506 cm-1; H NMR
1
(CDCl3) δ 1.70-1.80 (1H, m), 1.88-2.15 (5H, m), 2.11 (3H, s,
NCH3), 2.69 (1H, mH-2), 2.75 (2H, m, CH2Ph), 3.07 (1H, m,
H-5), 3.51 (1H, m, H-1), 3.95 (1H, d, J ) 4.9 Hz, H-3), 4.01
(2H, br, NH2), 4.10-4.25 (2H, m, OCH2), 5.32 (1H, s, OCHPh2),
6.65 (1H, d, J ) J ) 8.4 Hz, Ar-H), 6.90-7.05 (5H, m, Ar-
H), 7.17-7.28 (4H, m, Ar-H), 7.49 (1H, s, Ar-H) ppm; 13C
NMR (CDCl3) δ 24.6, 25.2, 33.6, 36.2, 41.7, 51.9, 61.0, 63.2,
65.1, 70.1, 80.3, 84.1, 114.6, 115.1, 115.4, 128.4, 128.5, 129.6,
129.9, 138.3, 139.1, 145.3, 160.4, 163.7, 172.4 ppm.
S-(+)-2â-Ca r bo(3-iod o-4-a zid op h en yl)eth oxy-3r-(bis[4-
flu or op h en yl]m eth oxy)tr op a n e (15). To a solution of com-
pound 14 (40 mg, 0.06 mmol) in a mixture of acetic acid (1
mL) and H2O (1 mL) was added NaNO2 (6 mg, 0.09 mmol),
and the mixture was stirred at 0 °C for 30 min. Then NaN3 (6
mg, 0.09 mmol) was added, and the mixture was stirred for
another 30 min at 0 °C. The mixture was diluted with H2O,
basified with saturated NaHCO3 solution, and extracted with
chloroform. The combined organic layer was dried over MgSO4
and concentrated. The residue was purified by column chro-
matography (CHCl3/MeOH/NH4OH, 97:3:1) to yield 26 mg
(63%) of 15 as an oil. [R]25 +3.1° (c 0.9, CHCl3); 1H NMR
D
(CDCl3) δ 1.74-1.80 (1H, m), 1.88-2.15 (5H, m), 2.10 (3H, s,
NCH3), 2.69 (1H, m, H-2), 2.84 (2H, m, CH2Ph), 3.08 (1H, m,
H-5), 3.48 (1H, m, H-1), 3.74 (1H, d, J ) 5.0 Hz, H-3), 4.23
(2H, m, OCH2), 5.33 (1H, s, OCHPh2), 6.95-7.06 (5H, m, Ar-
H), 7.21-7.26 (5H, m, Ar-H), 7.65 (1H, s, Ar-H) ppm; 13C
NMR (CDCl3) δ 24.6, 25.2, 33.9, 36.1, 41.7, 51.9, 61.0, 63.2,
64.5, 70.1, 80.3, 87.7, 115.2, 115.5, 118.3, 128.0, 128.4, 130.0,
136.6, 138.2, 138.4, 140.1, 140.4, 160.4, 163.7, 172.3 ppm. Anal.
(C30H29N4F2IO3) C, H, N.
(13) Newman, A. H.; Kline, R. H.; Allen, A. C.; Izenwasser, S.; George,
C.; Katz, J . L. Novel 4′- and 4′,4′′-Substituted-3R-(diphenyl-
methoxy)tropane Analogs Are Potent and Selective Dopamine
Uptake Inhibitors. J . Med. Chem. 1995, 38, 3933-3940.
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J . Med. Chem. 1994, 37, 2001-2010.
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855-862.
S-(+)-2â-Car bo(4-isoth iocyan atoph en yl)eth oxy-3r-(bis-
[4-flu or op h en yl]m eth oxy)tr op a n e (16). Compound 13 (50
mg, 0.1 mmol) was dissolved in a mixture of CHCl3 (6 mL)
and aqueous NaHCO3 solution (38 mg in 2.5 mL of H2O), and
the mixture was vigorously stirred. Freshly distilled CSCl2 (10
µL, 0.13 mmol) was added to the solution dropwise at 0 °C.
After the addition, stirring was continued for 3 h. Subse-
quently, the two layers were separated and the aqueous layer
was extracted with CHCl3. The combined organic layer was
dried over MgSO4 and concentrated. The residue was purified
by flash column chromatography (CHCl3/MeOH/NH4OH, 97:
3:1) to provide 44 mg (81%) of product 16 as an oil. Note that
compound 16 is unstable at room temperature and needs to
be stored at 0 °C. [R]25 +3.8° (c 1.2, CHCl3); IR 2100, 1728,
D
1505 cm-1; H NMR (CDCl3) δ 1.60-1.80 (1H, m), 1.88-2.20
1
(5H, m), 2.09 (3H, s, NCH3), 2.67 (1H, m, H-2), 2.90 (2H, m,
CH2Ph), 3.06 (1H, m, H-5), 3.46 (1H, m, H-1), 3.93 (1H, d, J )
4.77 Hz, H-3), 4.20-4.33 (2H, m, OCH2), 5.31 (1H, s, OCHPh2),
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(3′-substituted phenyl)-, 3â-(4′-substituted phenyl)-, and 3â-(3′4′-
disubstituted phenyl) tropane-2â-carboxylic acid methyl esters.
J . Med. Chem. 1994, 37, 2865-2873.
6.90-7.03 (4H, m, Ar-H), 7.10-7.30 (7H, m, Ar-H) ppm; 13
C
NMR (CDCl3) δ 24.6, 25.2, 34.6, 36.1, 41.7, 51.9, 61.0, 63.2,
64.4, 70.1, 80.4, 115.2, 115.5, 125.7, 128.3, 128.4, 129.6, 130.0,
137.6, 138.2, 138.4, 160.4, 163.7, 172.4 ppm.
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2002, 12, 1249-1252.
Ack n ow led gm en t. M.F.Z. was supported by a Na-
tional Institutes of Health Visiting Fellowship. This work
was funded by the National Institute on Drug Abuses

2916 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
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J M0300375