Synthesis and dopamine transporter affinity of the four stereoisomers of (±)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane

Article abstract of DOI:10.1021/jm9705061

All four stereoisomers of (±)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7- azabicyclo[2.2.1]heptane were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured in rat caudate-putamen tissue and found to be 100-3000-fold less potent (K(i) = 5- 96 μM) than cocaine and 2β-(methoxycarbonyl)-3β-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3α-phenyl isomers (6c, 6d) were more potent than the 3β-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2.1]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2β(methoxycarbonyl)-3-phenyltropanes.

Full text of DOI:10.1021/jm9705061

2430
J . Med. Chem. 1998, 41, 2430-2435
Syn th esis a n d Dop a m in e Tr a n sp or ter Affin ity of th e F ou r Ster eoisom er s of
(()-2-(Meth oxyca r bon yl)-7-m eth yl-3-p h en yl-7-a za bicyclo[2.2.1]h ep ta n e
Chunming Zhang,† Sari Izenwasser,‡ J onathan L. Katz,‡ Phyllis D. Terry,‡ and Mark L. Trudell*,†
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148 and NIDA Division of Intramural
Research, P.O. Box 5180, Baltimore, Maryland 21224
Received August 1, 1997
All four stereoisomers of (()-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane
were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter.
The in vitro binding affinities (Ki) of the 7-azabicyclo[2.2.1]heptane derivatives were measured
in rat caudate-putamen tissue and found to be 100-3000-fold less potent (Ki ) 5-96 µM)
than cocaine and 2â-(methoxycarbonyl)-3â-phenyltropane (2, WIN 35,065-2). Surprisingly, the
3R-phenyl isomers (6c, 6d ) were more potent than the 3â-phenyl isomers (6a , 6b). Molecular
modeling studies revealed that the rigid 7-azabicyclo[2.2.1]heptane derivatives possess
molecular topologies which are significantly different than the molecular topologies of the 2â-
(methoxycarbonyl)-3-phenyltropanes.
In tr od u ction
The elucidation of the pharmacophore for the cocaine
(1) binding site(s) on the dopamine transporter (DAT)
has been the subject of numerous investigations. From
these studies a great number of tropane and non-
tropane compounds have been synthesized and shown
to exhibit high affinity for binding sites on the DAT and
elicit potent inhibition of dopamine reuptake.1-25 Among
the tropanes that have been studied, the derivatives of
2â-(methoxycarbonyl)-3â-phenyltropane (WIN 35,065-
2, 2) have provided useful information toward under-
standing the structural criteria for high-affinity binding
and transporter selectivity at monoamine trans-
porters.1-16
As part of a study aimed at the structural elucidation
of the cocaine pharmacophore, it was of interest to
explore the effects of structural modification of the
tropane skeleton of 2 on molecular recognition at cocaine
binding sites on the DAT. Previous studies had re-
vealed that the 9-azabicyclo[3.3.1]nonane analogue 3
exhibited diminished activity at the DAT relative to the
tropane analogue 2.26 This demonstrated the sensitivity
of the cocaine binding site toward structural modifica-
ring relative to its corresponding acceptor site on the
tion of the C(6)-C(7) ethylene bridge of cocaine and the
transporter. Subsequently, the strength of the π-π or
importance of the tropane ring system for high-affinity
lipophilic interactions between the 3-phenyl ring and
binding.
the transporter was believed to be the source of the
Recently, Meltzer et al. have elegantly demonstrated
the importance of nonionic hydrogen-bond formation for
proper orientation of 2â-(methoxycarbonyl)-3â-phenyl-
tropanes (2) and 2â-(methoxycarbonyl)-3â-phenyl-8-
oxatropanes (4) at monoamine transporter binding
sites.16 From the results of this study it was proposed
that the nature of the hydrogen bond between the
transporter protein and the heteroatom at the 8-position
of the tropane ring affects the position of the 3-phenyl
observed potency and selectivity of the ligand. In
addition, it was shown that ligand potency among
derivatives of 2 was not affected by altering the stereo-
chemistry at C(3).16 The high affinity and selectivity
observed for the analogues of 2â-(methoxycarbonyl)-3R-
phenyltropane (5)16,27 was thought to be due to the
ability of the ligand to adopt a boat conformation such
that its molecular topology was not significantly differ-
ent from that determined for derivatives of 2.16 This
topology is defined by the relative proximity and ster-
eochemical orientation of the nitrogen atom, the centroid
of the phenyl ring, and the 2â-substituent.16 These
results clearly suggest that, in addition to minimum
structural requirements, a specific molecular topology
* Address correspondence to: Dr. Mark L. Trudell, Department of
Chemistry, University of New Orleans, New Orleans, LA 70148. Tel:
(504) 280-7337. FAX: (504) 280-6860. E-mail: MLTCM@UNO.EDU.
† University of New Orleans.
‡ NIDA Division of Intramural Research.
S0022-2623(97)00506-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/15/1998

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2431
Sch em e 1a
a
Reagents: (a) 90-95 °C; (b) Ni2B, EtOH; (c) Zn-Ag, MeOH; (d) PhMgBr, Et2O, -40 °C; then TFA, -78 °C; (e) HBr-AcOH; (f) HCHO,
NaBH3CN.
is necessary for high-affinity binding and transporter
To synthesize the 3R-isomers 6c and 6d an alternate
approach was developed from the 7-azabicyclo[2.2.1]-
heptene derivative 10 (Scheme 2). The Suzuki reaction
of 10 with phenylboronic acid in the presence of a
palladium(0) catalyst furnished the coupling product 14
in almost quantitative yield.33 Reduction of the carbon-
carbon double bond of 14 using magnesium in methanol
gave 15 as the major product (51%) along with 13
(32%).34 Conversion of 15 into 6c then proceeded in 83%
overall yield.
Finally, the 2R,3R-isomer 6d was prepared by hydro-
genation (40 psi) of 14 over 5% palladium on carbon in
methanol. The reaction was found to proceed stereo-
selectively to give the 2R,3R-isomer 16 in high yield
(95%). Conversion of 16 into 6d was then achieved in
78% yield.
selectivity. In addition, it seems that relative stereo-
chemistry is less important as long as the ligand can
adopt a stable conformation which meets the required
molecular topology of the binding site.
To further address the importance of the topology
imparted by the tropane ring of 2, 4, and 5 for molecular
recognition at cocaine binding site(s) on the DAT, we
have synthesized the ring-contracted analogues of 2, the
7-azabicyclo[2.2.1]heptane derivatives 6a -d . It was
envisaged that incorporation of the basic structural
features of 2-(methoxycarbonyl)-3-phenyltropane DAT
ligands into the rigid 7-azabicyclo[2.2.1]heptane ring
system would provide DAT ligands with well-defined
molecular topologies and perhaps provide additional
insight into the topological requirements of the DAT
pharmacophore. Herein we report the synthesis and
DAT binding affinity of the four stereoisomers of (()-
2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo-
[2.2.1]heptane (6).
Biology
Compounds 6a -d were tested for their ability to
displace bound [3H]WIN 35,428 from rat caudate-
putamen tissue. The Ki values reported in Table 1 are
inhibition constants derived for the unlabeled ligands.35
Previous studies have shown that, cocaine (1) and WIN
35,065-2 (2) modeled better for two binding sites than
for one; as a consequence, their high-affinity and low-
affinity Ki values are given in Table 1.35,36 The
7-azabicyclo[2.2.1]heptane derivatives 6a -d exhibited
monophasic binding; hence a single Ki value is reported
for each compound in Table 1. The inhibition of dopam-
ine uptake was not measured due to the low potency of
the stereoisomers 6a -d .
Ch em istr y
As illustrated in Scheme 1, the construction of the
7-azabicyclo[2.2.1]heptane ring system was achieved by
heating methyl 3-bromopropiolate (8)28 with a 4-fold
excess of N-(methoxycarbonyl)pyrrole (7)29 at 90-95 °C
for 33 h.30 This furnished the cycloadduct 9 in 56%
yield.31 Selective reduction of the least substituted
double bond of 9 was achieved by using nickel boride
and afforded 10 in 92% yield. Debromination of 10 with
Zn-Ag couple provided 11 in almost quantitative yield
(98%).32 Treatment of 11 with phenylmagnesium bro-
mide and subsequent workup with trifluoroacetic acid
at low temperature furnished a mixture of 2â-isomer
12 (41%) and 2R-isomer 13 (31%), which were easily
separated by chromatography. Removal of the N-
methoxycarbonyl group of 12 and N-methylation af-
forded the desired 2â,3â-isomer 6a in 58% overall yield.
The 2R,3â-isomer 6b was prepared in similar fashion
from 13.
Resu lts a n d Discu ssion
Despite the similar stereochemical orientations of the
3â-phenyl group and the 2â-methoxycarbonyl group in
2 relative to 6a , the latter displayed dramatically
reduced binding affinity for DAT. As shown in Table
1, the 2â,3â-isomer 6a was 2000-fold less potent than
the high-affinity binding components of 1 and 2. Of the

2432 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Notes
Sch em e 2a
a
Reagents: (a) PhB(OH)2, Na2CO3, Pd(OAc)2, PPh3, EtOH, benzene; (b) Mg, MeOH; (c) HBr-AcOH; (d) HCHO, NaBH3CN; (e) H2 (40
psi), 5% Pd/C, MeOH.
Ta ble 1. Ki Values of 7-Azabicyclo[2.2.1]heptane Derivatives
6a -d for the Inhibition of Bound [3H]win 35,428a
compd
Ki (µM)
compd
Ki (µM)
1b
0.032 ( 0.005
0.39 ( 0.22
0.033 ( 0.017
0.31 ( 0.22
6a c
6be
6cc
6d c
60.4 ( 4.8d
96.5 ( 42d
5.62 ( 0.39
18.9 ( 1.7
2b
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 35 and were collected under conditions identical with the
d
present ones. c Tested as the oxalate salt. Incomplete inhibition
at 100 µM; only 50% inhibition was observed. e Tested as the
hydrochloride salt.
four isomers, the 2â,3R-isomer 6c was the most potent
derivative, albeit 100-fold less potent than 1 and 2. It
is noteworthy that among the 7-azabicyclo[2.2.1]heptane
derivatives, the 3R-isomers 6c and 6d were considerably
more potent than the 3â-isomers 6a and 6b which
exhibited incomplete inhibition (50%) of [3H]WIN 35,-
428 at a concentration of 100 µM.
To address the low affinity observed for the 7-aza-
bicyclo[2.2.1]heptane derivatives 6a -d the molecular
topologies of the compounds were compared with those
of the tropane derivatives 2 and 5. To compare the
molecular topologies of the 7-azabicyclo[2.2.1]heptane
derivatives 6a and 6c with those of the tropanes 2 and
5, fully geometry-optimized structures were obtained
with SYBYL 6.0 molecular modeling software.37 Ini-
tially, the structures were energy-minimized by a
MAXIMIN2 force field. The minimized structures were
then geometry optimized with an AM1 (MOPAC) cal-
culation. The minimized structures were then aligned
by least-squares fitting of C(1), C(5), C(6), C(7), and N(8)
of 2 and 5 with C(1), C(4), C(5), C(6), and N(7) of 6a
and 6c using the FIT option of SYBYL 6.0.37
The differences between the molecular topologies of
the 7-azabicyclo[2.2.1]heptane derivatives 6a and 6c
and the tropane derivatives 2 and 5 are clearly evident
from the overlaid structures shown in Figure 1. The
most striking difference between the four molecules was
the intramolecular distance between the phenyl group
and the nitrogen atom. The phenyl groups of 6a and
F igu r e 1. (a, Top) Side view of overlaid structures 2 (cyan),
5 (yellow), 6a (green), and 6c (magenta). (b, Bottom) Top view
of overlaid structures 2 (cyan), 5 (yellow), 6a (green), and 6c
(magenta).
6c were found to be much closer to the nitrogen atom
than were the phenyl groups of 2 and 5. This suggests

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2433
3-Br om o-2,7-bis(m eth oxyca r bon yl)-7-a za bicyclo[2.2.1]-
h ep ta -2,5-d ien e (9). A mixture of N-(methoxycarbonyl)-
pyrrole (7)29 (9.2 g, 74 mmol) and methyl 3-bromopropiolate
(8)28 (2.4 g, 15 mmol) was stirred at 90-95 °C under an argon
atmosphere for 33 h. The resulting mixture was cooled to room
temperature and subjected to chromatography (EtOAc/petro-
leum ether; 1:12). The first fractions contained unreacted 7
(7.5 g), followed by the adduct 9 (2.4 g, 56% based on 7) as a
light yellow oil: IR (NaCl) 2959, 1717, 1617, 1445, 1339, 1226
that the molecular topologies of 6a and 6c are more
compressed than the tropane derivatives. The degree
to which the molecular topologies of 6a and 6c are
compressed can be quantified by measurement of the
nitrogen atom-phenyl centroid distance (N-PhC). From
the geometry-optimized structures the calculated N-PhC
distance for 6a was 4.2 Å and for 6c was 5.0 Å while
the N-PhC distances for 2 (5.6 Å)2 and 5 (5.5 Å) were
significantly longer.37 In addition, the spacial orienta-
tions of the phenyl groups of 6a and 6c were significanly
different relative to 2 and 5. The phenyl groups of 6a
and 6c are displaced from the molecular plane which
passes through the nitrogen atom and bisects the
molecule through the C(2)-C(3) and C(5)-C(6) bonds.
However, the phenyl groups of 2 and 5 are included in
the bisecting plane which passes through the nitrogen
atom, C(3), and the middle of C(6)-C(7) ethylene bridge.
(Figure 1b).
This molecular analysis suggests that despite similar
functional groups and relative stereochemistry, the
source of the low affinity of the 7-azabicyclo[2.2.1]-
heptane derivatives 6a -d is due to the unique molec-
ular topologies imparted by the rigid 7-azabicyclo[2.2.1]-
heptane ring system. It is likely that the compressed
topologies observed for 6a and 6c do not permit suf-
ficient penetration of the phenyl ring into the binding
site to elicit similar potencies for the 3-phenyltropanes
2 and 5. In addition, the large displacement of the
phenyl groups of 6a -d from the plane bisecting the
tropanes through C(3), N(8), and the middle of the C(5)-
C(6) bond may also contribute to the low affinity
observed for 6a and 6c. Among the 7-azabicyclo[2.2.1]-
heptane derivatives 6a -d a similar trend of the effect
of topology compression was observed. The less com-
pressed topologies of the 3R-isomers 6c and 6d are
believed to permit a slightly greater penetration of the
phenyl ring into the binding site which results in the
modest affinity observed for these ligands while the
more compressed 3â-derivatives 6a and 6b exhibit lower
affinity. This suggests that it may be possible to design
7-azabicyclo[2.2.1]heptane derivatives which could adopt
a molecular topology similar to the tropane analogues
and thus display high affinity for cocaine binding sites
on the DAT.
1
cm-1; H NMR (CDCl3) δ 7.14 (br s, 2H), 5.56 (s, 1H), 5.22 (s,
1H), 3.79 (s, 3H), 3.69 (s, 3H); 13C NMR (CDCl3) δ 162.5, 154.8,
143.8, 143.7, 141.1, 141.0, 74.4, 68.3, 53.1, 51.8; MS (CI, CH4)
m/z 290 (M+ + 1, 40), 258 (87), 256 (90), 208 (100). Anal.
(C10H10BrNO4) C, H, N.
3-Br om o-2,7-bis(m eth oxyca r bon yl)-7-a za bicyclo[2.2.1]-
h ep t-2-en e (10). To a solution of nickel(II) acetate tetrahy-
drate (3.0 g, 12 mmol) in ethanol/water (12 mL, 5:1) was added
dropwise with stirring under argon a solution of sodium
borohydride (0.46 g, 12.1 mmol) in ethanol (12 mL) at room
temperature. The resulting black slurry was stirred for an
additional 10 min. To the slurry was added a solution of 9
(700 mg, 2.42 mmol) in THF (12 mL) over 15 min followed by
dropwise addition of concentrated hydrochloric acid (2 mL, 24
mmol). The mixture was stirred for 24 h and then filtered
through
a pad of Celite. The filtrate was washed with
dichloromethane (20 mL) and carefully rendered basic (pH
8-9) using a saturated sodium bicarbonate solution. The
organic layer was separated and dried (Na2SO4). After evapo-
ration of the solvents, the residue was subjected to chroma-
tography (EtOAc/petroleum; 1:6) to give 10 (660 mg, 92%) as
a colorless oil: IR (NaCl) 1727, 1606, 1444, 1278, 1243, 788
cm-1 1H NMR (CDCl3) δ 5.05 (s, 1H), 4.79 (s, 1H), 3.79 (s,
;
3H), 3.66 (s, 3H), 2.00 (m, 2H), 1.39 (m, 2H); 13C NMR (CDCl3)
δ 162.2, 155.3, 136.9, 135.2, 68.4, 62.5, 52.9, 51.8, 25.8, 24.6;
MS (CI, CH4) m/z 292 (M+ + 1, 43), 290 (M+ + 1, 45), 260 (98),
258 (100). Anal. (C10H12BrNO4) C, H, N.
2,7-Bis(m eth oxyca r bon yl)-7-a za bicyclo[2.2.1]h ep ta n e-
2-en e (11). Aqueous 10% HCl (5 mL) was added to Zn dust
(710 mg, 11 mmol) with stirring. After 5 min, the liquid was
decanted and the Zn was washed with acetone (2 × 5 mL) and
ether (5 mL). A suspension of silver acetate (25 mg, 0.15
mmol) in boiling acetic acid (2 mL) was added with stirring.
After 1 min, the supernatant was decanted and the black Zn-
Ag couple was washed with acetic acid (3 mL), ether (4 × 5
mL), and methanol (5 mL). To the moist Zn-Ag couple was
added a solution of 10 (500 mg, 1.7 mmol) in methanol (2.5
mL). The resulting suspension was stirred at room temper-
ature and monitored by TLC. After 24 h, the metal residue
was filtered and washed with methanol. The filtrate was
evaporated under reduced pressure, and the residue was
partitioned between ether (5 × 10 mL) and 10% HCl (5 mL).
The combined ether layers were dried (Na2SO4) and evapo-
rated. The residue was purified by chromatography (EtOAc/
petroleum ether; 1:6) to afford 11 (360 mg, 98%) as a colorless
In summary, the results of this study indicate that
the molecular topology defined by stereoisomeric (()-
2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo-
[2.2.1]heptanes 6a -d is significanly different from that
defined by similarly substituted tropanes (e.g., 2 and
5). Due to the poor affinty of 6a -d , we conclude that
the 8-heterobicyclo[3.2.1]heptane ring system (tropane
and 8-oxatropane) is extremely important for imparting
a molecular topology among 2â-(methoxycarbonyl)-3-
phenyltropane derivatives that is recognized by the
cocaine binding site on the DAT.
oil: IR (NaCl) 1727, 1455, 1379, 1293, 793 cm-1 1H NMR
;
(CDCl3) δ 7.03 (s, 1H), 5.05 (s, 1H), 4.88 (s, 1H), 3.77 (s, 3H),
3.66 (s, 3H), 1.99 (m, 2H), 1.24 (m, 2H); 13C NMR (CDCl3) δ
163.3, 155.6, 144.3, 144.1, 61.1, 59.8, 52.8, 51.9, 24.3, 24.2; MS
(CI, CH4) m/z 212 (M+ + 1, 100), 180 (98). Anal. (C10H13NO4)
C, H, N.
2â,7-Bis(methoxycarbonyl)-3â-phenyl-7-azabicyclo[2.2.1]-
h ep ta n e (12) a n d 2r,7-bis(m eth oxyca r bon yl)-3â-p h en yl-
7-a za bicyclo[2.2.1]h ep ta n e (13). To a freshly prepared
solution of phenylmagnesium bromide (6.0 mmol) in ether (15
mL) at -40 °C was added dropwise a solution of 11 (630 mg,
3.0 mmol) in ether (8 mL). The reaction mixture was stirred
for an additional 2 h at - 40 °C, cooled to - 78 °C, quenched
with trifluoroacetic acid and allowed to warm to room tem-
perature. The mixture was then diluted with water (15 mL),
rendered to pH ) 7 with aqueous sodium bicarbonate and
extracted with ether (3 × 15 mL). The organic phase was dried
(Na2SO4) and separated by chromatography (EtOAc/petroleum
ether, 1:5), which afforded 13 (270 mg, 31%) followed by 12
(350 mg, 41%). The 2â,3â-isomer 12 was isolated as a colorless
Exp er im en ta l Section
All chemicals were purchased from Aldrich Chemical Co.,
Milwaukee, WI, unless otherwise noted. Ether and benzene
were dried by distillation from Na/benzophenone. Methanol
and acetone were dried by distillation over Drierite. Chro-
matography refers to flash chromatography on silica gel (silica
gel 60, 230-400 mesh, E. M. Science), and petroleum ether
refers to pentanes with a boiling point range of 30-60 °C.
Reported melting points are uncorrected. Elemental analyses
were obtained from Atlantic Microlabs, Inc., Norcross, GA.

2434 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
oil which solidified on standing: mp 88-89 °C; IR (NaCl) 1747,
Notes
and the water layer was then extracted with CH2Cl2 (4 × 20
mL). The combined organic layers were dried (K2CO3) and
evaporated under reduced pressure. The resulting residue was
purified by chromatography (MeOH/CH2Cl2, 1:10) to afford the
corresponding amine. To a stirred mixture of the amine (0.6
mmol) and aqueous formaldehyde (0.52 mL, 6.4 mmol, 37%)
in acetonitrile (10 mL) was added sodium cyanoborohydride
(80 mg, 1.3 mmol). The reaction mixture was stirred for 45
min. The solution was made neutral by the addition of glacial
acetic acid and then stirred for 2 h. The solution was then
made basic by the addition of aqueous Na2CO3 and extracted
with CH2Cl2 (4 × 10 mL). The combined organic extracts were
dried (Na2SO4) and concentrated under reduced pressure. The
residue was then purified by chromatography (acetone/
petroleum ether, 1:6). The spectral data for 6a -d are reported
for the freebase. The freebase was then converted into the
oxalate or hydrochloride salts to give white hygroscopic solids
used for microanalysis and in vitro testing.
1712, 1460, 1369, 753, 703 cm-1 1H NMR (CDCl3) δ 7.26-
;
7.16 (m, 5H), 4.67 (s, 1H), 4.45 (m, 1H), 3.76 (s, 3H), 3.28 (d,
J ) 9.9 Hz, 1H), 3.03 (d, J ) 9.9 Hz, 1H), 3.02 (s, 3H), 1.87
(m, 2H), 1.59 (m, 2H); 13C NMR (CDCl3) δ 171.1, 155.6, 140.2,
128.0, 127.9, 126.8, 61.3, 61.2, 57.2, 54.9, 52.6, 52.3, 50.9, 29.6,
28.3; MS (CI, CH4) m/z 290 (M+ + 1, 80), 258 (100). Anal.
(C16H19NO4) C, H, N. 13: colorless oil which solidified on
standing; mp 64-66 °C; IR (NaCl) 1740, 1712, 1465, 1369,
1
1182, 753, 703 cm-1; H NMR (CDCl3) δ 7.30-7.19 (m, 5H),
4.65 (br s, 1H), 4.37 (br s, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.31
(d, J ) 5.5 Hz, 1H), 3.11 (dd, J ) 4.6, 5.5 Hz, 1H), 1.83-1.60
(m, 4H); 13C NMR (CDCl3) δ 172.2, 155.7, 143.9, 128.9, 127.0,
126.7, 62.8, 58.2, 56.8, 52.6, 52.1, 50.3, 29.8, 24.9; MS (CI, CH4)
m/z 290 (M+ + 1, 100), 258 (22). Anal. (C16H19NO4) C, H, N.
2,7-Bis(m eth oxycar bon yl)-3-ph en yl-7-azabicyclo[2.2.1]-
h ep t-2-en e (14). To a solution of 10 (1.5 g, 5.0 mmol) and
benzeneboronic acid (0.73 g, 6.0 mmol) in ethanol-benzene
(1:5, 30 mL) were added 2 M Na2CO3 (5.0 mL, 10.0 mmol),
Pd(OAc)2 (55 mg, 0.25 mmol), and Ph3P (140 mg, 0.50 mmol)
under argon. The mixture was refluxed for 7 h under an argon
atmosphere. After the mixture was cooled to room tempera-
ture, water (10 mL) was added, and the resulting mixture was
extracted with EtOAc (3 × 10 mL). The combined organic
fractions were washed with brine and dried (Na2SO4). The
solvent was removed under reduced pressure, and the residue
was purified by chromatography (EtOAc/petroleum ether, 1:10)
to furnish 14 (1.4 g, 99%) as a colorless oil: IR (NaCl) 2969,
1717, 1606, 1446, 1288, 764, 698 cm-1; 1H NMR (CDCl3) δ 7.62
(m, 2H), 7.39 (m, 3H), 5.15 (s, 1H), 5.11 (s, 1H), 3.74 (s, 3H),
3.67 (s, 3H), 2.10 (m, 2H), 1.50 (m, 2H); 13C NMR (CDCl3) δ
164.0, 155.6, 131.7, 129.4, 128.7, 128.1, 65.6, 62.8, 52.8, 51.6,
26.0, 25.5; MS (CI, CH4) m/z 288 (M+ + 1, 19), 259 (58), 256
(100). Anal. (C16H17NO4) C, H, N.
2â-(Meth oxycar bon yl)-7-m eth yl-3â-ph en yl-7-azabicyclo-
[2.2.1]h ep ta n e (6a ): colorless oil (58%); IR (NaCl) 2959, 1743,
1601, 1217, 753, 708 cm-1; H NMR (CDCl3) δ 7.57-7.55 (m,
1
2H), 7.34-7.23 (m, 3H), 3.73 (d, J ) 2.8 Hz, 1H), 3.39 (d, J )
2.8 Hz, 1H), 3.17 (d, J ) 10.3 Hz, 1H), 3.09 (s, 3H), 2.95 (d, J
) 10.3 Hz, 1H), 2.47 (s, 3H), 2.09 (m, 2H), 1.53 (m, 2H); 13C
NMR (CDCl3) δ 172.1, 142.5, 128.5, 127.6, 126.2, 67.4, 62.2,
55.7, 53.4, 50.6, 34.7, 26.2, 25.2; MS (CI, CH4) m/z 246 (M+
1, 100), 214 (10); mp 144-145 °C (oxalate salt). Anal. (C15H19
+
-
NO2‚2C2H2O4) C, H, N.
2r-(Meth oxycar bon yl)-7-m eth yl-3â-ph en yl-7-azabicyclo-
[2.2.1]h ep ta n e (6b): colorless oil (50%); IR (NaCl) 1740, 1220,
750, 708 cm-1; H NMR (CDCl3) δ 7.45-7.43 (m, 2H), 7.29-
1
7.27 (m, 2H), 7.20 (m, 1H), 3.69 (s, 3H), 3.59 (t, J ) 4.4 Hz,
1H), 3.35 (d, J ) 4.2 Hz, 1H), 3.12 (d, J ) 5.6 Hz, 1H), 3.01
(dd, J ) 5.6, 4.2 Hz, 1H), 2.30 (s, 3H), 1.98-1.80 (m, 2H), 1.52-
1.40 (m, 2H); MS (CI, CH4) m/z 246 (M+ + 1, 100), 214 (15);
mp 225-226 °C (HCl salt). Anal. (C15H19NO2‚HCl‚0.1 H2O)
C, H, N.
2â,7-Bis(m et h oxyca r b on yl)-3r-p h en yl-7-a za b icyclo-
[2.2.1]h ep ta n e (15). A mixture of 14 (290 mg, 1.0 mmol) and
magnesium turnings (240 mg, 10 mmol) in methanol (10 mL)
was stirred at room temperature for 2 h. A solution of 2 N
HCl was carefully added until the excess magnesium dissolved
and the solution was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine, dried (Na2-
SO4), and evaporated under reduced pressure. The resulting
isomers were separated by chromatography (EtOAc/petroleum
ether; 1:8) which afforded 13 (93 mg, 32%) and the desired
compound 15 (148 mg, 51%) as a colorless oil: IR (NaCl) 1742,
2â-(Meth oxycar bon yl)-7-Meth yl-3r-ph en yl-7-azabicyclo-
[2.2.1]h ep ta n e (6c): colorless oil (83%); IR (NaCl) 1740, 1220,
750, 708 cm-1; 1H NMR (CDCl3) δ 7.34-7.17 (m, 5H), 3.86 (br
s, 1H), 3.73-3.65 (m, 4H), 3.51 (dd, J ) 4.6, 4.2 Hz, 1H), 2.65
(d, J ) 4.6 Hz, 1H), 2.34 (s, 3H), 1.94 (m, 1H), 1.60 (m, 1H),
1.35 (m, 2H); 13C NMR (CDCl3) δ 174.3, 139.7, 139.7, 128.2,
127.8, 127.8, 126.2, 66.5, 65.6, 52.1, 50.4, 34.9, 27.1, 20.5; MS
(CI, CH4) m/z 246 (M+ + 1, 100), 214 (15); mp 205-207 °C
(oxalate salt). Anal. (C15H19NO2‚1.5C2H2O4) C, H, N.
2r-(Meth oxycar bon yl)-7-m eth yl-3r-ph en yl-7-azabicyclo-
[2.2.1]h ep a tn e (6d ): colorless oil (78%); IR (NaCl) 1730, 1465,
1717, 1460, 1374, 1182, 743, 708 cm-1 1H NMR (CDCl3) δ
;
7.40-7.19 (m, 5H), 4.63 (br s, 1H), 4.54 (br s, 1H), 3.93 (dd, J
) 5.4, 5.0 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 2.81 (d, J ) 5.4
Hz, 1H), 1.88 (m, 1H), 1.55 (m, 3H); 13C NMR (CDCl3) δ 173.3,
155.7, 138.1, 128.5, 127.9, 60.7, 60.6, 52.6, 52.4, 51.8, 50.3, 30.1,
23.1; MS (CI, CH4) m/z 290 (M+ + 1, 100), 214 (10). Anal.
(C16H19NO4) C, H, N.
1253, 1182, 743, 713 cm-1; H NMR (CDCl3) δ 7.29-7.16 (m,
1
3H), 7.05-7.02 (m, 2H), 3.80 (dd, J ) 12.3, 4.0 Hz, 1H), 3.52-
3.34 (m, 6H), 2.43 (s, 3H), 2.31 (m, 1H), 1.79 (m, 1H), 1.73 (m,
1H), 1.62 (m, 1H); 13C NMR (CDCl3) δ 173.1, 138.7, 128.9,
128.0, 126.3, 67.7, 64.6, 51.1, 48.5, 47.9, 34.3, 22.6, 21.5; MS
(CI, CH4) m/z 246 (M+ + 1, 100), 214 (10); mp 188-189 °C
(oxalate salt). Anal. (C15H19NO2‚C2H2O4) C, H, N.
2r,7-Dim eth oxycar bon yl-3r-ph en yl-7-azabicyclo[2.2.1]-
h ep ta n e (16). To a solution of 14 (290 mg, 1.0 mmol) in
methanol (10 mL) was added 5% Pd/C (30 mg), and the
mixture was hydrogenated (40 psi) overnight. The catalyst
was removed by filtration and the solvent evaporated. The
residue was chromatographed (EtOAc/petroleum ether, 1:6)
to give 16 (280 mg, 95%) as a colorless oil: IR (NaCl) 1740,
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.
1714, 1460, 1349, 1187, 743, 708 cm-1 1H NMR (CDCl3) δ
;
7.30-7.20 (m, 3H), 7.08-7.05 (m, 2H), 4.52 (br s, 1H), 4.37
(br s, 1H), 3.78 (m, 1H), 3.74 (s, 3H), 3.40 (s, 4H), 2.43 (m,
1H), 1.88 (m, 2H), 1.62 (m, 1H); 13C NMR (CDCl3) δ 171.8,
155.7, 137.3, 128.5, 128.1, 126.6, 61.9, 59.0, 52.5, 51.1, 48.6,
48.5, 24.6, 23.6; MS (CI, CH4) m/z 290 (M+ + 1, 100), 258 (31),
127 (74). Anal. (C16H19NO4) C, H, N.
P r ep a r a tion of 6a -d (Gen er a l P r oced u r e). A solution
of the corresponding 7-(methoxycarbonyl)-7-azabicyclo[2.2.1]-
heptane derivative(1.2 mmol) in 33% HBr-HOAc (10 mL) was
stirred at room temperature and monitored by TLC. After 40
h, the solvent was removed under reduced pressure, the
residue was dissolved in CH2Cl2 (20 mL), and water (10 mL)
was added. Saturated aqueous Na2CO3 was carefully added
to adjust the pH to 10-11. The organic layer was removed,
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