Synthesis and dopamine transporter affinity of 2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane derivatives

Article abstract of DOI:10.1021/jm960507d

A series of 9-methyl-3β-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (K_i) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (K_i = 2-14 μM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.

Full text of DOI:10.1021/jm960507d

4744
J . Med. Chem. 1996, 39, 4744-4749
Syn th esis a n d Dop a m in e Tr a n sp or ter Affin ity of
2-(Meth oxyca r bon yl)-9-m eth yl-3-p h en yl-9-a za bicyclo[3.3.1]n on a n e Der iva tives
Zhengming Chen,† Sari Izenwasser,§ J onathan L. Katz,§ Naijue Zhu,‡ Cheryl L. Klein,‡ and Mark L. Trudell*,†
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, NIDA Intramural Research Program,
P.O. Box 5180, Baltimore, Maryland 21224, and Department of Chemistry, Xavier University of Louisiana,
New Orleans, Louisiana 70125
Received J uly 15, 1996X
A series of 9-methyl-3â-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were syn-
thesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT).
The conformation of the bicyclic structures and the stereochemistry of the substituents were
determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the
9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they
were found to be 100-fold (Ki ) 2-14 µM) less potent than cocaine and other tropane analogs.
From these results it is evident that the cocaine-binding site at the DAT is very sensitive to
structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and
cocaine-like compounds.
In tr od u ction
has been proposed that these ligands which access
alternative binding domains may be useful as treat-
ments for drug addiction. These drugs may inhibit
cocaine binding while not inhibiting dopamine uptake
at DAT and allow sufficient potentiation of the dopam-
inergic system to maintain extracellular concentrations
of dopamine.16-18
The pharmacologic spectrum of activity exhibited by
cocaine (1) has been shown to be mediated by occupation
of binding sites on biogenic amine transporters in
mammalian central nervous systems.1-3 The positive
reinforcing effect of 1 is believed to be due to inhibition
of dopamine uptake at dopamine transporters (DAT).4-6
A number of structure-activity relationship (SAR)
studies of cocaine analogs and 2-substituted-3â-aryltro-
panes have provided insight into the structural criteria
for high-affinity efficacious ligands at DAT.7-13 These
SAR studies have demonstrated profound stereochem-
ical effects and substituent effects at C(2), C(3), C(6),
C(7), and N(8) of the tropane nucleus of cocaine-related
drugs. From these studies the 2â-(methoxycarbonyl)-
3â-phenyltropane derivatives 2 have been found to be
among some of the most potent ligands for cocaine-
binding sites at DAT.7,9
As part of an ongoing program of research aimed at
the structural elucidation of the cocaine pharmacophore
and the development of treatments for cocaine abuse,
it was of interest to explore the effects of structural
modification of the tropane ring system of the potent
2â-(methoxycarbonyl)-3â-phenyltropane derivatives. The
(1R)-2â-(m et h oxyca r bon yl)-9-m et h yl-3â-ph en yl-9-
azabicyclo[3.3.1]nonane (6) is a homolog of 2a (WIN
35,065-2)19 and was envisaged as an attractive drug
candidate to explore the effect of structural modification
of the C(6)-C(7) methylene bridge of the 2â-(methoxy-
carbonyl)-3â-phenyltropane analogs. In addition, on the
basis of studies with C(6)- and C(7)-methoxy pseudoco-
caine analogs which have been described as weak
cocaine antagonists,10 the stereoisomers of 6 were also
of interest. Herein we wish to report the synthesis,
structural features, and DAT binding affinity of a series
In addition to tropane derivatives, several other
classes of ligands have been reported to be potent
inhibitors of [3H]cocaine binding at DAT. These ligands
include mazindol (3),14 GBR compounds 4,15 and some
benztropine analogs 5.16,17 The diversity of structures
which demonstrate high binding affinity has led to the
formulation of a cocaine-binding site model which is
composed of alternative and possibly multiple binding
domains.7,10,16,17 These ligands competitively inhibit
[3H]cocaine binding yet, on a molecular level, probably
interact with the DAT differently from each other. It
* Corresponding author. Tel: (504) 280-7337. Fax: (504) 280-6860.
E-mail: MLTCM@UNO.EDU.
† University of New Orleans.
‡ Xavier University of Louisiana.
§ NIDA Intramural Research Program.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
S0022-2623(96)00507-9 CCC: $12.00 © 1996 American Chemical Society

Synthesis and DAT Affinity of Azabicyclononanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4745
Sch em e 1a
Sch em e 2a
a
Reagents: (a) H2O, Na2HPO4, 24 h, then HCl, ∆, 1 h; (b) NaH,
(CH3O)2CO, cyclohexane, ∆; (c) tartaric acid.
of 9-methyl-3-phenyl-2-substituted-9-azabicyclo[3.3.1]-
nonane derivatives.
Ch em istr y
The 9-azabicyclo[3.3.1]nonane is an important sub-
structure of a variety of compounds which possess
neuroleptic,20,21 antiparkinsonian,22 and hypotensive
activity.23 As a result, the synthesis of 9-azabicyclo-
[3.3.1]nonane derivatives has been the subject of nu-
merous studies. The most efficient synthetic method
for the preparation of the 9-azabicyclo[3.3.1]nonane ring
system is via the synthesis of 9-methyl-9-azabicyclo-
[3.3.1]nonan-3-one (7, pseudopellitierene), an alkaloid
obtained from the bark of the pomegranate tree.24,25 The
construction of the 9-azabicyclo[3.3.1]nonane ring was
achieved with a modification of Robinson’s procedure
for the preparation of 7.25 As illustrated in Scheme 1,
the biomimetic reaction of the glutaraldehyde, methyl-
amine, and acetonedicarboxylic acid gave 7 in 80% yield.
The ketone 7 was then converted into the â-keto ester
8 with dimethyl carbonate using an established
procedure.16,26-28 Spectroscopic data (1H and 13C NMR)
suggested that the â-keto ester 8 existed almost entirely
in the enol tautomeric form 9 (Scheme 1).
Racemic 9 was easily resolved into the enantiomers
(+)- and (-)-9 by recrystallization with L-(+)- and D-
(-)-tartaric acid, respectively.28 The absolute configu-
ration of (+)-9 was assigned as having C(1R)-stereo-
chemistry analogous to the (+)-isomer of the correspond-
ing 8-azabicyclo[3.2.1]octane system,16,26 while the (-)-9
was assigned as having C(1S)-stereochemistry. Un-
equivocal assignment of the absolute configuration of
(+)-9 was achieved by X-ray crystallographic analysis
of the (+)-9‚L-tartrate salt.29
a
Reagents: (a) (CF3SO2)2O, pyridine; (b) HCO2H, Pd(OAc)2,
PPh3, Et3N, DMF, 60 °C; (c) PhMgBr (1 equiv), Et2O, -40 °C, TFA,
-70 °C; (d) PhMgBr (2 equiv), Et2O, -40 to 25 °C, TFA, -70 °C;
(e) LiCl, Na2CO3, Pd2(dba)3, DME, C6H5B(OH)2; (f) PtO2, H2 (50
psi), EtOH.
products 6 and 12 in 30% and 35% yields, respectively,
after chromatography. In addition, treatment of 11 with
2 equiv of phenylmagnesium bromide afforded the
phenyl ketones 13 (36%) and 14 (54%) (Scheme 2).
Alternatively, the enantiomers 15 and 16 were prepared
in similar fashion from (-)-9 (Scheme 2).
A coupling reaction of the vinyl triflate 10 with
phenylboronic acid in refluxing dimethoxyethane using
tris(dibenzylideneacetone)dipalladium(0) as a catalyst
gave 17 in 80% yield.33 Hydrogenation (50 psi) of 17
over PtO2 provided 18 as the major product (30%) along
with unreacted 17 and trace amounts of other isomers.
1H and 13C NMR spectroscopy has been found to be
very useful for the stereochemical and conformational
analysis of the 9-azabicyclo[3.3.1]nonane derivatives.34-37
Accordingly, the stereochemical and conformational
assignments of stereoisomers of 6, 12-16, and 18 were
made on the basis of NMR data in similar fashion. For
compounds 6 and 12-16, H(2), H(3), H(4a) and H(4e)
were easily differentiated from other ring protons
because of the C(2)- and C(3)-substituents. The values
of the coupling constants of J 2,3, J 3,4a, and J 3,4e were
consistent with the conformations assigned to related
With (+)-9 in hand conversion into the vinyl triflate
10 was achieved in high yield (81%) by addition of
trifluoromethanesulfonic anhydride to a solution of (+)-9
and pyridine in CH2Cl2 (Scheme 2).30 The vinyl triflate
10 was then converted into the alkene 11 using Cacchi’s
procedure in analogous fashion to the synthesis of
anhydroecgonine methyl ester recently reported by
Carroll et al.31,32 Conjugate addition of 1 equiv of
phenylmagnesium bromide to 11 provided the desired

4746 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Chen et al.
Ta ble 1. Ki Values for Displacement of Bound [3H]WIN 35,428
(2b)a
did not warrant further study of these compounds as
dopamine uptake inhibitors.
analog
Ki (µM)
Unlike the SAR of (-)-cocaine and (R)-2â-substituted-
3â-phenyltropane derivatives, the C(2)-stereoisomer 12
and the enantiomers 15 and 16 were equipotent to 6,
albeit about 100-fold less potent than 2a . No stereose-
lectivity or enantioselectivity for binding sites on the
DAT was observed for these compounds. In addition,
the phenyl ketone derivatives 13 and 14 exhibited Ki
values on the same order magnitude as 6. It is
noteworthy that the 2R-isomer 14 was slightly more
potent than any of the other analogs. This suggests that
the binding criteria for the 2-substituted-3â-phenyl-9-
azabicyclo[3.3.1]nonane analogs are different than that
of the corresponding (R)-2â-substituted-3â-phenyltro-
pane derivatives. Therefore similar to the results
observed for difluoropine (5a ), in which the lipophilic
3R-diarylmethoxy substituent is thought to occupy the
lipophilic region of the binding site associated with the
2â-substituents of (R)-cocaine analogs, the increased
lipophilicity in the 2R-position of 14 may allow the
ligand to adopt a conformation which facilitates bind-
ing.16 Moreover, based on the diverse number of
structures which bind to the cocaine-binding site and
recent reports which identify binding site heterogeneity,
it is possible to speculate that compounds such as 5a
and 14 may bind at a different domain(s) of a single
binding site or bind to an alternative binding site on
the DAT.16,17,38
Similar to the SAR of cocaine, the enol (+)-9 and the
2R,3R-isomer 18 were the least potent of the 9-azabicyclo-
[3.3.1]nonane analogs.7 In addition, the SAR of the
9-azabicyclo[3.3.1]nonane derivatives was similar to the
findings reported by Kozikowski et al. for the racemic
series of C(6)- and C(7)-methoxy cocaine analogs.10
These analogs were also found to exhibit low binding
affinities (micromolar range) at DAT. Clearly from
these two independent studies, it is evident that struc-
tural modification of the methylene bridge of 2â-
substituted-3â-phenyltropane derivatives 2 has a pro-
found effect on binding affinity. In fact, the binding site
appears to be more sensitive to substituents in this
region of the molecule than any other region of the 2â-
substituted-3â-phenyltropane.
1b
0.032 ( 0.005
0.39 ( 0.22
0.033 ( 0.017
0.31 ( 0.22
4.60 ( 0.51
2a b
6c
(+)-9d
12c
13c
14c
15c
16c
18c
>100e
5.73 ( 0.57
3.97 ( 0.36
1.91 ( 0.10
3.45 ( 0.31
3.47 ( 0.35
13.9 ( 2.01
a
All values are the mean ( SEM of three experiments per-
formed in triplicate. b The Ki values for these drugs are reproduced
from ref 38 and were collected under conditions identical with the
present ones. c Tested as the fumarate salt. Tested as the tartrate
d
salt. e No inhibition at concentrations up to 100 µM.
bicyclic ring systems.34-37 A value of ∼13 Hz indicated
a trans-diaxial relationship, while ∼6 Hz corresponded
to a cis-axial-equatorial or a trans-diequatorial rela-
tionship. For example, in compound 12, H(3) exhibited
a trans-diaxial relationship with H(2) (J ) 12.5 Hz) and
H(4a) (J ) 12.7 Hz) and a cis-axial-equatorial relation-
ship with H(4e) (J ) 6.5 Hz). Similar to the 2â-
(methoxycarbonyl)-3â-phenyltropanes, the 2â-ester group
resulted in an upfield shift of the NCH3 signal (1H NMR)
of 6 (δ 2.53 ppm) relative to the NCH3 signal of 12 (δ
2.61 ppm).19 Based on coupling constants it is believed
that in solution 6 and 12 exist in a chair-chair
conformation while 18 was observed to exist in a chair-
boat conformation. The major difference between these
two conformations was the 13C NMR chemical shifts of
C(7). An upfield shift of the C(7) signal of 18 (δ 15.2
ppm) relative to 6 (δ 21.5 ppm) and 12 (δ 28.3 ppm),
respectively, indicated that the 3R-phenyl group forced
the unsubstituted ring to flip into a boat conformation
to alleviate steric interactions. This observation was
consistent with Wiseman’s conformational study of the
9-azabicyclo[3.3.1]nonane derivatives.34,35 The struc-
tural assignments of 12 and 14 determined by NMR
were unequivocally confirmed by X-ray crystallogra-
phy.29
In conclusion, the results of this study clearly dem-
onstrate that the unsubstituted methylene bridge [C(6)-
C(7)] of cocaine and cocaine-like compounds appears to
be a vital feature for molecular recognition at the
cocaine-binding site on DAT. The sensitivity of the
binding site toward structural modification of the meth-
ylene bridge [C(6)-C(7)] of derivatives of cocaine sug-
gests that it may be possible to attenuate the potency
as well as the activity (agonist to antagonist) of cocaine-
binding site ligands with the appropriate use of sub-
stituents at C(6) and/or C(7). In addition, further
studies of the effects of substituents at C(6) and C(7) of
2-substituted-3-aryltropane derivatives may provide
additional information about the apparent heterogeneity
of the cocaine-binding site at DAT.
Biologica l Resu lts a n d Discu ssion
The 9-azabicyclo[3.3.1]nonane derivatives were tested
in vitro for their ability to displace bound [3H]WIN
35,428 (2b) from rat caudate-putamen tissue.38 The Ki
values reported in Table 1 are dissociation constants
derived for the unlabeled ligands. Both cocaine (1) and
2a modeled better for two binding sites than for one,
and therefore two Ki values are given in Table 1.11,38 In
contrast compounds 6, 9, and 12-18 did not model for
two sites better than for one. The low binding affinity
of the 9-azabicyclo[3.3.1]nonane derivative 6 was very
surprising considering that the difference between 2a
and 6 was only the addition of a single methylene unit
which resulted in a 100-fold decrease in binding site
affinity. Comparison of the Ki values of 6 with high-
affinity 2â-(methoxycarbonyl)-3â-phenyltropanes and of
13 with 2â-acyl-3â-aryltropanes clearly illustrates the
sensitivity of the binding site to structural modification
of the unsubstituted methylene bridge of the 8-azabicyclo-
[3.2.1]octane ring system of cocaine analogs.7,9 The low
binding affinity of the 9-azabicyclo[3.3.1]nonane analogs
Exp er im en ta l Section
All chemicals and reagents not otherwise noted were
purchased from Aldrich Chemical Co., Milwaukee, WI. Dichlo-
romethane (E. M. Science) was dried over P2O5 and distilled
under nitrogen before use. Tetrahydrofuran (THF; Baker) and
benzene (E. M. Science) were dried by distillation from sodium

Synthesis and DAT Affinity of Azabicyclononanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4747
and benzophenone. Methanol was dried by distillation over
magnesium metal. Dimethyl sulfoxide (DMSO) was dried by
distillation under high vacuum over CaH2. Ethyl acetate (E.
M. Science) and 30-60 °C petroleum ether (E. M. Science)
were distilled prior to use. Chromatography refers to flash
chromatography with silica gel (Silica Gel 60, 230-400 mesh;
E. M. Science). Silica gel TLC plates (E. M. Science; Kiesel
gel 60, F254, 0.2 mm layer, plastic and/or glass back) were
purchased from Curtin-Matheson Scientific and visualized
under UV light. NMR spectra were recorded using a Varian
Gemini 300 MHz spectrometer. IR spectra were recorded on
a Perkin-Elmer 2000 FT-IR spectrometer. The fumarate salts
of 6, 12-16, and 18 were obtained from a mixture of the base
(1 equiv) and fumaric acid (1 equiv) in hot 2-propanol. The
salt was recrystallized twice from 2-propanol. Optical rota-
tions of compounds 6, 12-16, and 18 were determined as the
fumarate salt and measured on a Rudolph Autopol III pola-
rimeter. Melting points were recorded on a Buchi melting
point apparatus and are uncorrected. Elemental analyses
were performed by Atlantic Microlab Inc., Norcross, GA.
9-Meth yl-9-a za bicyclo[3.3.1]n on a n -3-on e (P seu d op el-
letier in e, 7). See ref 25 for experimental details: (61 g, 80%);
ethanol. Ethanol was then removed under reduced pressure,
and the residue was recrystallized from an acetone/water
mixture (10:1, 110 mL) until a constant rotation was obtained.
This afforded the (-)-2-(methoxycarbonyl)-9-methyl-9-azabicyclo-
[3.3.1]nonan-3-one tartrate as a white crystalline solid. The
solid was recrystallized until a constant rotation was ob-
tained: [R]21 ) -15° (c 1.0, H2O); mp 64-66 °C. Anal.
D
(C11H17NO3‚C4H6O6‚1/2H2O) C, H, N.
The free base was generated by the same procedure de-
scribed above to give (-)-2-(methoxycarbonyl)-9-methyl-9-
azabicyclo[3.3.1]nonan-3-one [(-)-9] (1.1 g, 10%) as a white
solid: mp 91-94 °C; [R]21 ) -28° (c 1.0, CH3OH). Anal.
D
(C11H17NO3) C, H, N.
(+)-2-(Meth oxyca r bon yl)-9-m eth yl-9-a za bicyclo[3.3.1]-
n on -2-en e 3-Tr iflu or om eth ylsu lfon a te (10). To a stirred
solution of (+)-9 (10.8 g, 51 mmol) and pyridine (20 mL) at 0
°C was added trifluoromethanesulfonic anhydride (9.3 mL, 55
mL) was added via syringe. The solution was allowed to warm
slowly to room temperature and maintained at room temper-
ature for 12 h. The volume of the reaction mixture was
reduced on a rotoevaporatory instrument to about 15 mL, and
then the pink solution was directly chromatographed (ethyl
acetate:petroleum ether 2:1) to furnish 10 as a yellow oil (14.1
g, 81%): 1H NMR (CDCl3) δ 3.89 (br, 1H), 3.80 (s, 3H), 3.22
(br, 1H), 2.77 (dd, J ) 19.5, 7.2 Hz, 1H), 2.36 (s, 3H), 2.17-
1.53 (m, 7H); 13C NMR (CDCl3) δ 164.1, 150.7, 121.9, 120.5,
116.2, 57.0, 53.6, 52.1, 41.6, 32.6, 28.2, 28.1, 14.6. Anal.
(C12H16F3NO5S) C, H, N.
1
mp 48-52 °C (lit.24,25 mp 47-53 °C); H NMR (CDCl3) δ 3.27
(br s, 2H), 2.80-2.68 (dd, J ) 16.6, 6.4 Hz, 2H), 2.59 (s, 3H),
2.25 (s, 1H), 2.19 (s, 1H), 1.93 (m, 2H), 1.60-1.46 (m, 3H), 1.44
(m, 1H); 13C NMR (CDCl3) δ 210.7, 55.8, 42.0, 41.4, 29.7, 16.2.
2-(Me t h oxyca r b on yl)-9-m e t h yl-9-a za b icyclo[3.3.1]-
n on a n -3-on e (9). A solution of 7 (23 g, 0.15 mol) in cyclo-
hexane (140 mL) was added dropwise to a mixture of pre-
washed (petroleum ether) NaH (12 g, 60% dispersion, 0.30 mol)
and dimethyl carbonate (25 mL, 0.30 mol) in cyclohexane (60
mL) at a gentle reflux. Methanol (0.5 mL) was then added at
the end of the addition. The reaction mixture was heated at
reflux until effervescence ceased. Water (250 mL) was added
after the reaction mixture had cooled to room temperature.
The layers were separated, and the cyclohexane layer was
washed with additional water (2 × 100 mL). The combined
aqueous layers were saturated with NH4Cl (120 g) and
extracted with dichloromethane (8 × 100 mL). The combined
organic extracts were dried (K2CO3), and the solvent was
removed under reduced pressure to afford 8. The â-keto ester
8 was found to exist almost entirely (>97%; 8 was not observed
by 1H NMR) in the tautomeric enol form 9 as a white
crystalline material (26 g, 81%): mp 126-127 °C; 1H NMR
(CDCl3) δ 12.1 (s, 1H), 3.74 (s, 3H), 3.61 (s, 1H), 3.07 (s, 1H),
2.65 (dd, J ) 19.2, 7.3 Hz, 1H), 2.32 (s, 3H), 1.93-1.70 (m,
3H), 1.53-1.43 (m, 4H); 13C NMR (CDCl3) δ 171.7, 96.9, 53.2,
52.6, 51.4, 41.8, 32.6, 29.3, 28.1, 14.9. Anal. (C11H17NO3) C,
H, N.
(+)-2-(Meth oxyca r bon yl)-9-m eth yl-9-a za bicyclo[3.3.1]-
n on -2-en e (11). A solution of 10 (13 g, 42 mmol), triethyl-
amine (24 mL), palladium acetate (0.3 g), and triphenylphos-
phine (0.6 g) in DMF (80 mL) was stirred under nitrogen.
Formic acid (4 mL, 99%) was added dropwise via syringe over
2-3 min. The resulting mixture was warmed in an oil bath
at 60 °C for 1 h. During this period the mixture became black.
The contents of the flask were poured into water (50 mL) and
extracted with ether (5 × 100 mL). The combined etheral
portions were dried (K2CO3), and the solvent was removed
under reduced pressure. The residue was purified by chro-
matography (petroleum ether:ether:triethylamine, 4:5:1) to
furnish 11 as a colorless oil (6.9 g, 89%): 1H NMR (CDCl3) δ
7.12 (t, J ) 3.69 Hz, 1H), 3.60 (s, 3H), 3.51 (br, 1H), 2.83 (br,
1H), 2.45 (m, 1H), 2.18 (s, 3H), 1.80-1.27 (m, 7H); 13C NMR
(CDCl3) δ 166.5, 139.9, 128.6, 53.7, 51.4, 51.2, 41.4, 32.7, 27.8,
25.8; [R]22 ) +4.4° (c 0.20, CHCl3). Anal. (C11H17NO2) C, H,
D
N.
(+)-2â-(Me t h o x y c a r b o n y l)-9-m e t h y l-3â-p h e n y l-9-
a za bicyclo[3.3.1]n on a n e (6). To a 300 mL flame-dried,
round-bottomed flask were added anhydrous ether (120 mL)
and phenylmagnesium bromide (3.50 mL, 10.5 mmol, 3 M in
Et2O) under nitrogen. The solution was cooled to -40 °C, and
11 (1.95 g, 10.0 mmol) in anhydrous ether (120 mL) was added
slowly. The reaction mixture was stirred for 2 h at -40 °C
and cooled to -78 °C; the reaction was quenched with
trifluoroacetic acid (1 mL, 12 mmol), and the mixture was
allowed to warm to room temperature. The yellow mixture
was then diluted with water and acidified to pH ) 1 with
concentrated HCl, and the etheral portion was discarded. The
aqueous solution was basified with NH4OH (pH >10) and
extracted with dichloromethane (3 × 100 mL). The organic
phase was dried (Na2SO4), the solvent was removed under
reduced pressure, and the residue was chromatographed
(petroleum ether:ether:triethylamine, 4:5:1) to afford a color-
less oil (0.82 g, 31%): 1H NMR (CD2Cl2) δ 7.29-7.15 (m, 5H),
3.76 (ddd, J ) 13.5, 5.6, 5.6 Hz, 1H, H3), 3.39 (s, 3H, OCH3),
3.23 (d, J ) 5.3 Hz, 1H, H5), 3.14 (d, J ) 5.6 Hz, 1H, H2),
3.03 (br, 1H, H1), 2.85 (dt, J ) 13.3, 12.8, 5.1 Hz, 1H, H4a),
2.53 (s, 3H, NCH3), 2.31-2.02 (m, 3H), 1.88 (dd, J ) 12.6, 5.1
Hz, 1H, H4e), 1.74 (m, 1H), 1.48 (dd, J ) 14.6, 6.57 Hz, 1H),
1.31 (m, 1H); 13C NMR (CD2Cl2) δ 173.3, 144.8, 128.2, 127.3,
126.0, 56.6, 53.0, 52.5, 51.2, 41.1, 36.7, 32.6, 21.5, 21.2, 20.6.
R esolu t ion of (()-2-(Met h oxyca r b on yl)-9-m et h yl-9-
a za bicyclo[3.3.1]n on a n -3-on e (9). (+)-2-(Methoxycarbonyl)-
9-methyl-9-azabicyclo[3.3.1]nonan-3-one [(+)-9]. L-(+)-Tartaric
acid (9.0 g, 0.060 mol) was added to (()-9 (12.6 g, 0.060 mol)
in ethanol (100 mL). Ethanol was removed under reduced
pressure after all the tartaric acid had dissolved. The residue
was recrystallized from acetone/water (10:1, 440 mL) to afford
(+)-2-(methoxycarbonyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-
one tartrate as a pale crystalline solid. The solid was
recrystallized until a constant rotation was obtained [R]21
)
D
+13° (c 1.0, H2O); mp 60-63 °C. Anal. (C11H17NO3‚C4H6O6‚
1/2H2O) C, H, N.
The salt 9‚C4H6O6 was dissolved in saturated Na2CO3 (50
mL), and the free base was extracted with dichloromethane
(2 × 100 mL). The combined extracts were dried (K2CO3) and
then concentrated to afford (+)-2-(methoxycarbonyl)-9-methyl-
9-azabicyclo[3.3.1]nonan-3-one [(+)-9] (4.2 g, 30%) as a white
solid: mp 93-95 °C; [R]21 ) +28° (c 1.0, CH3OH). Anal.
D
(C11H17NO3) C, H, N.
(-)-2-(Meth oxyca r bon yl)-9-m eth yl-9-a za bicyclo[3.3.1]-
n on a n -3-on e [(-)-9]. The filtrates from the resolution with
L-(+)-tartaric acid were concentrated to dryness. The residue
obtained was dissolved in saturated Na2CO3 (50 mL), and the
free base was extracted with dichloromethane (3 × 100 mL).
The dried (K2CO3) organic extract was concentrated to dryness
under reduced pressure. The residue (2.1 g, 0.11 mol) and D-(-
)-tartaric acid (1.5 g, 0.13 mol) were dissolved in absolute
6‚C4H4O4: mp 127-128 °C; [R]22 ) +5.0° (c 1.0, CH3OH).
D
Anal. (C17H23NO2) C, H, N.
(+)-2r-M e t h o x y c a r b o n y l-9-m e t h y l-3â-p h e n y l-9-
a za bicyclo[3.3.1]n on a n e (12). Compound 12 was obtained
after 6 in the elution sequence as a colorless oil (0.96 g, 35%).

4748 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Chen et al.
1H NMR (CD2Cl2) δ 7.29-7.16 (m, 5H), 3.76 (ddd, J ) 13.5,
12.7, 6.4 Hz, 1H, H3), 3.51 (s, 3H, OCH3), 3.35 (dd, J ) 12.3,
5.0 Hz, 1H, H2), 3.14 (br, 1H, H1), 2.86 (br, 1H, H5), 2.61 (s,
3H, NCH3), 2.08-1.80 (m, 4H), 1.71 - 1.45 (m 4H); 13C NMR
(CDCl3) δ 174.7, 146.9, 128.8, 127.8, 126.6, 56.0, 53.3, 51.7,
46.8, 41.2, 40.3, 33.7, 28.3, 25.4, 20.2. 12‚C4H4O4: mp 148-
h. The catalyst was removed by filtration through Celite and
washed with ethanol (2 × 5 mL). After removal of the solvent
under reduced pressure, the residue was chromatographed
(triethylamine:petroleum ether, 1:9) to afford 18 as a colorless
oil (0.2 g, 35%): 1H NMR (CD2Cl2) δ 7.28-7.13 (m, 5H), 3.72
(dd, J ) 10.3, 8.0 Hz, 1H, H2), 3.51 (ddd, J ) 13.3, 8.0, 5.0
Hz, 1H, H3), 3.34 (s, 3H, OCH3), 3.30 (br, 1H, H1), 3.08 (br,
1H, H5), 2.56 (s, 3H, NCH3), 2.41 (ddd, J ) 13.5, 13.3, 5.0 Hz,
1H, H4a), 2.23-2.15 (m, 2H), 2.02 -1.90 (m, 2H), 1.42 (m, 1H),
1.13 (d, J ) 13.5 Hz, 1H, 4He), 1.00 (m, 1H); 13C NMR (CDCl3)
δ 173.2, 143.0, 127.9, 127.7, 125.8, 52.8, 51.3, 50.7, 49.6, 40.2,
151 °C; [R]22 ) +2.2° (c 1.2, CH3OH). Anal. (C17H23NO2) C,
D
H, N.
(+)-2â-Ben zoyl-9-m eth yl-3â-p h en yl-9-a za bicyclo[3.3.1]-
n on a n e (13). To a 300 mL flame-dried, round-bottomed flask
were added anhydrous ether (120 mL) and phenylmagnesium
bromide (10.0 mL, 30.0 mmol, 3 M in Et2O). The solution was
cooled to -40 °C, and 11 (2.92 g, 15.0 mmol) in anhydrous
ether (120 mL) was added slowly. The reaction mixture was
stirred for 1 h at -40 °C. The solution was allowed to warm
up to room temperature and stirred for 12 h. The reaction
mixture was then cooled to -78 °C, the reaction quenched with
trifluoroacetic acid, and the mixture allowed to warm to room
temperature. The yellow mixture was then diluted with water
and acidified to pH ) 1 with concentrated HCl, and the etheral
portion was discarded. The aqueous solution was basified with
NH4OH (30%) and extracted with dichloromethane. The
organic phase was dried (Na2SO4), the solvent was removed
under reduced pressure, and the residue was purified by
chromatography (petroleum ether:ether:triethylamine, 4:5:1)
to furnish 13 as a white solid (1.4 g, 35%): 1H NMR (CD2Cl2)
δ 7.74 (d, J ) 7.4 Hz, 2H), 7.48 (t, J ) 7.2 Hz, 1H), 7.41-7.32
(m, 4H), 7.22 (t, J ) 7.5 Hz, 2H), 7.08 (t, J ) 7.2 Hz, 1H), 4.20
(d, J ) 5.9 Hz, 1H), 3.91 (m, 1H), 3.15-3.00 (m, 3H), 2.42 (s,
3H), 2.41-1.57 (m, 7H); 13C NMR (CD2Cl2) δ 199.6, 145.2,
132.6, 128.9, 128.2, 127.3, 125.8, 55.9, 52.9 52.8, 41.2, 37.2,
35.1, 26.8, 22.6, 20.4, 15.2. 18‚C4H4O4: mp 130-132 °C; [R]22
D
) +10.8° (c 1.0, CH3OH). Anal. (C17H23NO2‚1/2H2O) C, H, N.
Ack n ow led gm en t. We are grateful to the National
Institute on Drug Abuse (NIDA First Award R29
DA08055) for the financial support of this research. We
also wish to thank Mr. Brett Heller and Ms. Lu Espina
for technical assistance.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data, ORTEP drawings, and tables of bond distances,
bond angles, and positional parameters for (+)-9‚L-tartrate,
12, and 14 (29 pages). Ordering information is given on any
current masthead page.
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33.2, 21.4, 21.2, 20.8. 13‚C4H4O4: mp 135-138 °C; [R]22
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)
D
(+)-2r-Ben zoyl-9-m eth yl-3â-p h en yl-9-a za bicyclo[3.3.1]-
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(CD2Cl2) δ 7.86 (d, J ) 8.6 Hz, 2H), 7.52 (t, J ) 7.0 Hz, 1H),
7.42 (t, J ) 7.3 Hz, 2H), 7.34 (d, J ) 7.8 Hz, 2H), 7.23 (t, J )
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14‚C4H4O4: mp 164-165 °C; [R]22 ) +4.6° (c 0.5, CH3OH).
D
Anal. (C22H25NO) C, H, N.
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(-)-2â-(Me t h o x y c a r b o n y l)-9-m e t h y l-3â-p h e n y l-9-
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D
N.
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D
N.
(-)-2 -(M e t h o x y c a r b o n y l )-9 -m e t h y l -3 -p h e n y l -9 -
a za bicyclo[3.3.1]n on -2-en e (17). A solution of (+)-10 (3.43
g, 10.0 mmol), Na2CO3 (15 mL, 2 M), 1-phenylboronic acid (2.47
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neacetone)dipalladium (0.2 g, 0.5 mmol) in DME (35 mL) was
heated to reflux with vigorous stirring. After 2 h the reaction
mixture was cooled to room temperature and concentrated
under reduced pressure. The residue was chromatographed
(triethylamine:petroleum ether, 1:9) to afford (-)-17 as an oil
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7.3 Hz, 2H), 3.73 (br, 1H), 3.41 (s, 3H), 3.07 (br, 1H), 2.67 (dd,
J ) 19.8, 7.2 Hz, 1H), 2.41 (s, 3H), 2.09-1.52 (m, 7H); 13C NMR
(CDCl3) δ 168.8, 147.4, 141.9, 127.9, 127.2, 126.6, 126.5, 56.1,
52.6, 51.1, 41.6, 33.0, 31.6, 28.5, 15.2; free base [R]22D) -14.0°
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Synthesis and DAT Affinity of Azabicyclononanes
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