Synthesis and nicotinic acetylcholine receptor affinity of bivalent tropane-3-carboxylates

Article abstract of DOI:10.1002/jhet.5570440629

(Chemical Equation Presented) A series of diol di-(tropane-3α- carboxylate) esters and diol di-(tropane-3β-carboxylate) esters were synthesized from 3-tropene-3-carboxylic acid and tropane-3β-carboxylic acid, respectively. The bivalent tropane-3-carboxylates were evaluated for their ability to inhibit [³H]cytisine binding at rat brain nicotinic acetylcholine receptors (nAChRs). In general the (3β,3β′)- isomers were more potent than (3α,3α′)-isomer and the (3β,3β′)-decyl derivative (n = 10, K_i = 145 nM) exhibited the most potent affinity for nAChRs of the series.

Full text of DOI:10.1002/jhet.5570440629

Nov-Dec 2007
1425
Synthesis and Nicotinic Acetylcholine Receptor Affinity of Bivalent
Tropane-3-Carboxylates
Suhong Zhang[a], Sari Izenwasser[b], Dean Wade[b], Jie Cheng[a], Ying Liu[a],
Liang Xu[a] and Mark L. Trudell*[a]
[a] Department of Chemistry, University of New Orleans
New Orleans, LA 70148
[b] Department of Psychiatry and Behavioral Sciences
University of Miami School of Medicine, Miami FL 33136
E-mail: mtrudell@uno.edu
Received February 1, 2007
N
N
N
N
O
O
O
O
n
O
O
O
O
n
(3ꢀ, 3ꢀ')
(3ꢁ, 3ꢁ')
A series of diol di-(tropane-3ꢀ-carboxylate) esters and diol di-(tropane-3ꢁ-carboxylate) esters were
synthesized from 3-tropene-3-carboxylic acid and tropane-3ꢁ-carboxylic acid, respectively. The bivalent
tropane-3-carboxylates were evaluated for their ability to inhibit [3H]cytisine binding at rat brain nicotinic
acetylcholine receptors (nAChRs). In general the (3ꢁ,3ꢁ')-isomers were more potent than (3ꢀ,3ꢀ')-isomer
and the (3ꢁ,3ꢁ')-decyl derivative (n = 10, Ki = 145 nM) exhibited the most potent affinity for nAChRs of
the series.
J. Heterocyclic Chem., 44, 1425 (2007).
been reported, the bivalent ligand typically exhibited
significantly diminished potency relative to the
monomeric congener. Bivalent epibatidine derivatives 1,
were reported to exhibited a 40-350-fold decrease in
affinity relative to epibatidine [8,9]. The paucity of
bivalent compounds that bind to neuronal nAChRs with
high affinity, led us to consider neuromuscular nAChR
ligands as lead compounds for delevopment of a new
bivalent ligand system. Recently, Gyermek and coworkers
reported the bisquaternary ammonium tropine diester (2)
as a new class of neuromuscular blocking (NMB) agents
with modest side effects [10]. Bivalent tropane
compounds such as 2, have been extensively studied as
NMB agents at neuromuscular nAChRs [11]. Therefore it
was envisaged that a bis-tropane scaffold would be a
useful starting point for the development of novel bivalent
neuronal nAChR ligands.
INTRODUCTION
Neuronal nicotinic acetylcholine receptors (nAChRs)
have long been the target for the development of
therapeutic agents for tobacco addiction, smoking
cessation, muscle relaxation and antihypertension [1,2].
Recently, nAChRs have been identified as potential
targets for the development of new therapeutic agents for
the treatment of a number of other central nervous system
(CNS) diseases and disorders which include Alzheimer's
Disease, Parkinson's Disease, Tourette syndrome, anxiety
and depression [2-4]. Unfortunately, to date there are few
neuronal nAChR agents in which the therapeutic value of
the drug significantly overwhelms the side effects. Side
effects such as cardiovascular and gastrointestinal
dysfunction, addiction, neuromuscular effects and
seizures have limited the use of nAChR agents in drug
therapies. Therefore, the search for potent and selective
nAChR agents is an extremely important endeavor that
will provide pharmacological tools for the study of
nAChR function and lead to new therapeutic agents and
medications for the treatment of a variety of neurological
diseases.
Neuromuscular nAChRs have been well characterized
and differ significantly from neuronal nAChRs in
structure and function [2,12]. As a result, ligand structures
can be quite different for these two classes of receptors.
However despite these differences, at the onset of this
study the focus was to design a new series of bivalent
neuronal nAChR ligands using a bis-tropane scaffold. To
this end, we envisaged two structural modifications of 2
that were necessary to achieve the goal of neuronal
nAChR affinity. As part of our design rationale it was
necessary to develop lipophilic congeners that would
The use of bivalent compounds has been proven to be a
successful approach for the development of compounds
with improved potency and selectivity for a variety of
receptors in the CNS [5-7]. However, there have been few
reports of bivalent compounds exhibiting neuronal
nAChR affinity [8,9]. Of the bivalent systems that have

1426
S. Zhang, S. Izenwasser, D. Wade, J. Cheng, Y. Liu, L, Xu, M. L. Trudell
Vol 44
tropene-3-carboxylic acid (4). The acid 4 was readily
prepared from 2-tropinone using procedures previously
developed in our laboratory [14]. Conversion of 4 into the
corresponding acid chloride with thionyl chloride
followed by esterification with the appropriate diol
furnished the corresponding diesters 5a and 5b.
Subsequent hydrogenation of diesters 5a and 5b afforded
the desired 3ꢀ,3ꢀ'-sterochemistry of 6a and 6b in good
overall yields. The ethylene derivative the (3ꢀ,3ꢁ')-
ethylene glycol di-(tropane-3-carboxylate) (7a) was also
obtained as a side product in 17 % yield, while the
propylene congener 7b was not present in sufficient
quantities to isolate in pure form. Overall, this indirect
route for formation of the 3ꢀ,3ꢀ'-isomers was found to
minimize formation of mixed 3,3'-stereoisomers.
Cl
Cl
N
N
N
N
8
1
Cl
Cl
Cl
Cl
N
N
2Br
O
O
O
O
O
2 (3ꢀ,3ꢀ')
N
N
Scheme 1
O
O
N
O
3
CO2H
Figure 1
4
1) SOCl2, CHCl3
reflux
2) HO(CH2)nOH, DMAP
pyridine
penetrate into the brain. The quaternary ammonium
nitrogen atom of 2 was not consistent with the goal of a
CNS active compound. Therefore, the tertiary nitrogen
atom of tropane was deemed an ideal moiety to meet the
criteria of blood brain barrier permeability. Secondly, of
the reported tropane analogues that bind to nicotinic
acetycholine ion channel complexes, the acetoxy
derivatives of 2-, 3- and 6-tropine have been shown to be
generally more selective for neuronal muscarinic
receptors [13]. However, the constitutional isomers, the
corresponding carbomethoxy derivatives have been
reported to be more selective for neuronal (ꢀ4ꢁ2)
nicotinic receptors [13]. In lieu of these results, it was of
interest to alter the connectivity of the ester attachment in
2 and explore the structure-activity relationships of simple
tethered tropane-3-carboxylate derivatives. To this end, a
series of 3,3'-diol di-(tropane-3-carboxylate) derivatives 3
were identified as targets for synthesis. Herein we
describe the synthesis and neuronal nAChR affinity of a
series 3,3'-diol di-(tropane-3-carboxylate) derivatives.
N
N
O
O
O
n
O
5a n = 2
5b n = 3
H2(60 psi)
10% Pd/C
CH3OH
N
N
(3ꢀ, 3ꢀ')
O
O
O
O
n
6a n = 2
6b n = 3
N
+
N
RESULTS AND DISCUSSION
(3ꢀ,3ꢁ')
O
The 3ꢀ,3ꢀ'-diol tropane-3-carboxylates 6a and 6b were
selected as the initial targets due to the structural and
stereochemical similarity to 2. Previous attempts at direct
esterification of 3ꢀ-tropane-3-carboxylic acid resulted in
complex product mixtures due to the propensity of the 3ꢀ-
carboxylate to epimerize and furnish the more stable 3ꢁ-
tropane-3-carboxylic acid [14]. Therefore, as illustrated in
Scheme 1, a 3ꢀ,3ꢀ'-diol tropane-3-carboxylates 6a and
6b were prepared via an indirect method from the 2-
O
O
n
O
7a n = 2
7b n = 3
The corresponding (3ꢁ,3ꢁ')-diol di-(tropane-3-carbox-
ylate) congeners 9a and 9b were prepared from 3ꢁ-
tropane-3-carboxylic acid (8) [14]. Treatment of 8 with
thionyl chloride and concomitant diesterification with the

Nov-Dec 2007
Synthesis of Bivalent Tropane-3-Carboxylates
1427
of the tether length on the binding affinity of the 3ꢁ,3ꢁ'-
corresponding diol in pyridine with 10% 4-dimethyl-
aminopyridine (DMAP) furnished 9a (71%) and 9b (60%)
in good yields. Under these conditions no mixed 3,3'-
stereoisomers (e.g. 7a,b) were observed.
diol di-(tropane-3-carboxylate) derivatives.
Table 1
Inhibition of [3H]cytisine binding.
Scheme 2
Cmpd [a]
R
Ki (nM)[b]
N
N
6a
6b
7a
9a
9b
9c
-(CH2)2-
-(CH2)3-
-(CH2)2-
-(CH2)2-
-(CH2)3-
-(CH2)4-
43%[c]
24%[c]
2,570 ± 630
3,430 ± 1,500
835 ± 100
247 ± 24
(3ꢀ, 3ꢀ')
O
O
R
O
O
9a-j
9d
9e
t-CH2CH=CHCH2-
-(CH2)5-
1,090 ± 110
575 ± 63
9f
-(CH2)6-
-(CH2)7-
-(CH2)8-
-(CH2)9-
560 ± 35
546 ± 27
621 ± 70
259 ± 28
1) SOCl2, CHCl3
reflux
2) HOROH, DMAP
pyridine
9g
9h
9i
9j
10a
10b
-(CH2)10-
-(CH2)3CH3
-(CH2)9CH3
145 ± 2
477 ± 24
2254 ± 470
N
O
[a]Tested as the oxalate salt. [b]All values are the mean ±SEM of three
experiments, each performed in triplicate. [c]Percent inhibition at
highest dose tested (100 μM).
OH
8
1) SOCl2, CHCl3
reflux
2) ROH, DMAP
pyridine
The 3ꢁ, 3ꢁ'-diol di-(tropane-3-carboxylate) derivatives
9c-j were prepared using the procedure described above
from 8 and the corresponding commercially available
diols (Scheme 2). The effect of tether length on the
binding affinity of the bis-tropane esters was quite
striking. The (3ꢁ,3ꢁ')-decyl diester 9j was found to be the
most potent compound of the series and was 24-fold more
potent than the ethylene diol congener 9a.
N
O
OR
10a R = CH2CH2CH2CH3
10b R =CH2(CH2)8CH3
Within the class of the 3ꢁ,3ꢁ'-congeners the binding
affinities of were not incrementally proportional to the
tether length. The decyl (9j) and butyl (9c) analogues
exhibited the most potent affinity. Intermediate tether
lengths (C5-C8) afforded compounds that were less
favorable for binding and compounds with shortened
tethers (C2-C3) exhibited some of the lowest potency of
the series. The binding affinities of 9a-j corresponded
to the tether length in the following order:
C10>C4ꢀC9>C5ꢀC6ꢀC7ꢀC8>C3>C2. In addition it
appears that the more rigid tether of 9d (Ki = 1,090 nM)
was not as readily accommodated by the nAChR ion
complex as was the more flexible saturated analogue 9c
(Ki = 259 nM). These results suggest that the length of the
tether may not only be important for maintaining the
proper distance between the tropane residues but may also
be important for obtaining a conformation with molecular
topology favorable for interaction at binding sites at
neuronal nAChR ion channels. The high affinity of the
decyl analogue 9j relative to the other congeners is
consistent with conformational activity relationships
described for several classes of NMB agents [17].
However, this is in contrast to the structure-activity
The binding affinities of the diol di-(tropane-3-
carboxylate) esters summarized in Table 1, were
determined by the inhibition of [3H]cytisine binding in
homogenates of rat striatum [15]. There are a variety of
nAChRs subtypes that exist in the central nervous system;
however, the ꢀ4ꢁ2-subtype are the predominant nAChR
subtypes in rat striatum tissue and [3H]cytisine is selective
for this subtype [16]. Therefore, the data presented in
Table 1 principally represents the compounds affinity at
ꢀ4ꢁ2-subtype receptors. Surprisingly the 3ꢀ,3ꢀ'-isomers
6a and 6b exhibited low affinity for nAChRs. Compounds
6a and 6b did not fully inhibit [3H]cytisine binding at the
highest dose tested (100 μM), hence the binding affinities
are reported as the percent inhibition at 100 μM.
Alternatively, 3ꢁ-stereochemistry at one or both tropane
residues (7a, 9a and 9b) increased nAChR affinity
significantly. In addition, it was noted that increasing the
tether length by one methylene unit decreased the binding
affinity of the (3ꢀ,3ꢀ')-isomer 6a while the binding
affinity of the (3ꢁ,3ꢁ')-isomer 9b was increased four-fold
over 9a. This prompted further investigation of the effects

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S. Zhang, S. Izenwasser, D. Wade, J. Cheng, Y. Liu, L, Xu, M. L. Trudell
Vol 44
The amorphous solids were then dried thoroughly under reduced
pressure (0.1 mm Hg) at 65°C.
relationships of bivalent epibatidine analogues in which
the decyl analogues exhibited the lowest affinity for ꢀ4ꢁ2
subtype nAChRs [8]. Presumably this difference results
from the diffenent connectivity of the tethering units to
Ethylene glycol bis-(trop-2-ene-3-carboxylate) (5a). To
finely powdered (4) [14] (1.0 g, 6.0 mmol) in a 50 ml round
bottom flask were added chloroform (10 ml) and thionyl
chloride (1.8 ml, 24 mmol). The reaction was refluxed for 3 h
under nitrogen. The solvent was removed under reduced
pressure and the residue was flashed twice with benzene to
afford the acid chloride. Without further purification, the crude
acid chloride was added slowly to a vigorously stirred solution
of diol (2.4 mmol) and anhydrous pyridine (3 ml). After
complete addition, the mixture was heated to 110 °C under
nitrogen for 16 h. The mixture was cooled to room temperature
and water (10 ml) and dichloromethane (10 ml) were added to
dissolve the mixture. The organic layer was separated and the
aqueous phase was extracted with dichloromethane (3 ꢂ 10
ml). The organic layers were combined, dried (sodium sulfate)
and concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel-dichloromethane:
methanol: triethylamine, 80:2:1, v/v). to afford 760 mg of 5a
(88%) as a white solid. mp 76-78 °C; ir: 1715 (C=O), 1639
(C=C) cm-1; 1H nmr: ꢃ 7.0 (d, 2H J = 5.6 Hz), 4.35 (s, 4H),
3.45 (t, 2H, J = 5.6 Hz), 3.36 (t, 2H, J = 5.6 Hz), 2.67 (dd, 2H,
J = 18, 4.0 Hz), 2.36 (s, 6H), 2.29-2.15 (m, 2H), 2.14-2.07 (m,
2H), 1.95 (d, 2H, J = 18 Hz), 1.87 (td, 2H, J = 11, 2.4 Hz),
1.56-1.51 (m, 2H); 13C nmr: ꢃ 166.2 (2), 142.4(2), 125.9(2)
61.9(2), 58.8(2), 57.0(2), 36.2(2), 33.0(2), 30.3(2), 29.5 (2).
Anal. Calcd for C20H28N2O4: C, 66.64; H, 7.83; N, 7.77. Found:
C, 66.42; H, 7.96; N, 7.87.
the bicyclic amine moieties.
For the epibatidine
derivatives 1, the tether is directly connected to the
nitrogen atoms, which results in a linear separation of the
nitrogen atoms and closely approximates the separation of
the binding sites on the ion channel. However for the
tropanes, the tether is five atoms removed from the
nitrogen atom. As such the relative orientation of the two
nitrogen atoms can be quite varied. It is believed that the
longer tethers offer greater conformational freedom and
facilitate orientation of bulky tropane units into a
conformation that is favorable for interaction at nAChRs.
To confirm that the potency of the bivalent ligands was
impart due to tethering of the tropane residues, the mono
esters 10 were prepared (Scheme 2) and evaluated at
nAChRs. The butyl ester 10a (Ki = 477 nM) was only 2-
fold less potent than the bivalent congener 9c, while the
decyl ester 10b (Ki = 2254 nM) exhibited a 16-fold
decrease in affinity relative to the bivalent ester 9j.
Although these data indicated that there is little difference
between the mono and bivalent ligands 10a and 9c, the
effect of tethering the tropane residues appears to be
significant for the decyl analogues and suggests that the
decyl tether is optimum for this series for molecular
recognition of a bis-tropane scaffold at neuronal nAChRs.
In summary, we have synthesized and identified a new
class of bivalent neuronal nAChR ligands and have
demonstrated that a ten-carbon tether between two
tropane-3ꢁ-carboxylate residues afforded a compound
with nanomolar affinity for nAChRs. These novel
bivalent compounds will undoubtedly be useful as lead
compounds and pharmacological probes to explore the
structure-activity relationships of nAChR ion channel
complexes. Further evaluation of these and other bivalent
nAChR ligands is under investigation and will be reported
in due course.
1,3-Propanediol bis-(trop-2-ene-3-carboxylate) (5b). To
finely powdered (4)[14] (3.1 g, 18.5 mmol) in a 100 ml round
bottom flask were added chloroform (300 ml) and thionyl
chloride (6 ml, 80 mmol). The reaction was refluxed for 3 h
under nitrogen. The solvent was removed under reduced
pressure and the residue was flashed twice with toluene to afford
the acid chloride. Without further purification, the crude acid
chloride was added together with 4-dimethylaminopyridine (30
mg) to a vigorously stirred solution of 1,3-propanediol (0.53 ml,
7.4 mmol) and anhydrous pyridine (10 ml). After complete
addition, the mixture was stirred under nitrogen at room
temperature for 24 h. Water (20 ml) and dichloromethane (20
ml) were added to dissolve the mixture. The organic layer was
separated and the aqueous phase was extracted with dichloro-
methane (3 ꢂ 20 ml). The organic layers were combined, dried
(sodium sulfate) and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel-
dichloromethane: methanol: triethylamine, 80:2:1, v/v) to afford
1.9 g of 5b (71%) as a light brown oil. 1H nmr: ꢃ 7.01 (d, 2H, J
= 5.6), 4.21 (t, 4H, J = 12.4 Hz), 3.41 (t, 2H, J = 5.6 Hz), 3.35 (t,
2H, J = 5.6 Hz), 2.64 (d, 2H, J = 18 Hz), 2.35 (s, 6H), 2.19-2.03
(m, 8H), 1.95-1.90 (m, 2H), 1.54 (m, 2H); 13C nmr: ꢃ 166.6,
141.8, 126.3, 61.0 (2), 58.9(2), 57.1(2), 36.1(2), 33.1(2), 30.4(2),
29.5(2), 28.0. Anal. Calcd for C21H30N2O4: C, 67.35; H, 8.07; N,
7.48. Found: C, 67.46; H, 8.08; N, 7.50.
EXPERIMENTAL
All new compounds were characterized as the free base by 1H
nmr and 13C nmr. The nmr spectra were recorded on a Varian-
400 MHz spectrometer at ambient temperature in deuterio-
chloroform with tetraamethylsilane as an internal standard. The
oxalate salts were characterized by elemental analysis. C, H, N
analysis were determined by Atlantic Microlabs, Inc., Norcross,
GA. Melting points were recorded on a Hoover Mel-Temp
apparatus and are uncorrected
General Procedure for the Preparation of Oxalate Salts.
To a stirred solution of the bis-tropane (1 equiv.) in a
tetrahydrofuran (10 ml) was added a solution of oxalic acid (2.2
equiv.) in tetrahydrofuran. The mixture was then cooled to 0 °C
and allowed to stand for several hours. The white solid was
filtered under vacuum and rinsed with several portions of ether.
General Procedure for the Synthesis of Diol bis(tropane-
3ꢀ-carboxylate) (6). A suspension of (5) (1.0 g) and 10 %
palladium on carbon (150 mg) in methanol (10 ml) was
hydrogenated (60 psi) at room temperature for 3 days. The
catalyst was removed by filtration and the filtrate was
concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel-dichloromethane:methanol:
triethylamine, 80:2:1, v/v). The ir and nmr spectra were recorded

Nov-Dec 2007
Synthesis of Bivalent Tropane-3-Carboxylates
1429
for the freebase. The freebase was converted into the oxalate salt
for analysis.
the acid chloride. Without further purification, the crude acid
chloride was added together with 4-dimethylaminopyridine
(10%) to a vigorously stirred solution of diol (0.4 equiv.) and
anhydrous pyridine (10 equiv.). After complete addition, the
mixture was stirred and heated to dissolve any remaining solids.
Heating and stirring were continued under nitrogen for 24 h to
maintain a homogeneous mixture. The mixture was allowed to
cool to room temperature, then water and dichloromethane were
added to dissolve any solids present in the mixture. The organic
layer was separated and the aqueous phase was extracted with
dichloromethane. The organic layers were combined, dried
(sodium sulfate) and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel-
dichloromethane: methanol: triethylamine, 80:2:1, v/v) to afford
9b-j as an oil. The ir and nmr spectra were recorded for the
freebase. The freebase was converted into the oxalate salt for
analysis.
1,3-Propanediol bis(tropane-3ꢂ-carboxylate) (9b). This
compound was isolated as a light brown oil (60%) and converted
into the oxalate salt 1H nmr: ꢁ 4.11 (t, 4H, J = 12.4 Hz), 3.27
(brs, 4H), 2.63-2.57 (m, 2H), 2.35 (s, 6H), 2.10-1.89 (m, 12H),
1.71-1.59 (m, 6H); 13C nmr: ꢁ 175.4(2), 60.8(2), 60.4(4),
39.8(2), 34.4(4), 33.1(2), 27.9, 26.1(4). Anal. Calcd for
C21H34N2O4 •2C2H2O4: C, 53.76; H, 6.86; N, 5.03. Found: C,
53.11; H, 7.03; N, 4.94.
1,4-Butanediol bis(tropane-3ꢂ-carboxylate) (9c). This
compound was isolated as a light brown oil (66%) and converted
into the oxalate salt. 1H nmr: ꢁ 4.07 (brs, 4H), 3.32 (brs, 4H),
2.65-2.56 (m, 2H), 2.38 (s, 6H), 2.12-2.10 (m, 4H), 2.05-1.97
(m, 4H), 1.73-1.64 (m, 12H); 13C nmr: ꢁ 174.7(2), 63.7(4),
60.5(2), 39.2(2), 33.8(4), 32.4(2), 25.6(4), 25.0(2). Anal. Calcd
for C22H36N2O4•2C2H2O4•H2O: C, 52.88; H, 7.17; N, 4.74.
Found: C, 52.92; H, 7.21; N, 4.94.2-Butene-1, 4-diol
bis(tropane-3ꢂ-carboxylate) (9d). This compound was isolated
as a light brown oil (73%) and converted into the oxalate salt. 1H
nmr: ꢁ 5.70 (t, 2H, J = 8.4Hz), 4.64 (d, 4H, J = 4.8 Hz), 3.20
(brs, 4H), 2.64-2.55 (m, 2H), 2.29 (s, 6H), 2.06-2.03 (m, 4H),
1.94-1.87 (m, 4H), 1.67-1.62 (m, 4H), 1.59-1.53 (m, 4H); 13C
nmr: ꢁ 175.0(2), 128.0(2), 60.3(4), 59.8(2), 39.7(2), 34.2(4),
32.9(2), 26.1(4). Anal. Calcd for C22H34N2O4 •2C2H2O4•H2O: C,
53.06; H, 7.19; N, 4.76. Found: C, 54.86; H, 7.23; N, 5.00.
1,5-Pentanediol bis(tropane-3ꢂ-carboxylate) (9e). This
compound was isolated as a light brown oil (63%) and converted
into the oxalate salt. 1H nmr: ꢁ 4.04 (t, 4H, J = 13.2 Hz), 3.19 (brs,
4H), 2.63-2.54 (m, 2H), 2.29 (s, 6H), 2.06-2.04 (m, 4H), 1.94-1.84
(m, 4H), 1.66-1.54 (m, 12H), 1.42-1.34 (m, 2H); 13C nmr: ꢁ
175.5(2), 64.1(2), 60.4(4), 39.8(2), 34.4(4), 33.2(2), 28.2(2),
26.1(4), 22.4. Anal. Calcd for C23H38N2O4 •2C2H2O4•1/2H2O: C,
54.45; H, 7.28; N, 4.70. Found: C, 54.60; H, 7.23; N, 4.80.
1,6-Hexanediol bis(tropane-3ꢂ-carboxylate) (9f). This
compound was isolated as a light brown oil (68%) and converted
into the oxalate salt. 1H nmr: ꢁ 4.04 (t, 4H, J = 13.2), 3.19 (brs,
4H), 2.62-2.54 (m, 2H), 2.29 (s, 6H), 2.06-2.03 (m, 4H), 1.94-
1.87 (m, 4H), 1.67-1.54 (m, 12H), 1.39-1.33 (m, 4H); 13C nmr: ꢁ
175.5(2), 64.2(2), 60.4(4), 39.8(2), 34.4(4), 33.1(2), 28.5(2),
26.1(4), 25.5(2). Anal. Calcd for C24H40N2O4•2C2H2O4•H2O: C,
54.39; H, 7.50; N, 4.53. Found: C, 54.60; H, 7.81; N, 4.56.
1,7-Heptanediol bis(tropane-3ꢂ-carboxylate) (9g). This
compound was isolated as a light brown oil (70%) and converted
into the oxalate salt. 1H nmr: ꢁ 4.04 (t, 4H, J = 13.2 Hz), 3.19
(brs, 4H), 2.62-2.54 (m, 2H), 2.29 (s, 6H), 2.05-2.02 (m, 4H),
1.93-1.87 (m, 4H), 1.67-1.54 (m, 12H), 1.34-1.32 (m, 6H); 13C
Ethylene glycol bis(tropane-3ꢀ-carboxylate) (6a). This
compound was isolated as a colorless liquid (72%) and
1
converted into the oxalate salt. Ir: 1727 (C=O) cm-1; H nmr: ꢁ
4.34 (s, 4H), 3.07 (t, 4H, J = 3.4 Hz), 2.55 (tt, 2H, J = 8.4, 1Hz),
2.23 (s, 6H), 2.21 (ddd, 4H, J = 14.0, 2.0, 1 Hz), 1.95 (ddd, 4H, J
= 14, 8, 3.2 Hz), 1.93-1.86 (m, 4H), 1.57-1.52 (m, 4H); 13C nmr:
ꢁ 175.9 (2), 62.6 (4), 60.3 (2), 40.4 (2), 33.3 (2), 31.5 (4), 24.7
(4). Anal. Calcd for C20H32N2O4•2C2H2O4·H2O: C, 51.24; H,
6.81; N, 4.98. Found: C, 51.16; H, 6.91; N, 5.02.
1,3-Propanediol bis(tropane-3ꢀ-carboxylate) (6b). This
compound was isolated as a light brown oil (35%) and converted
into the oxalate salt. ir: 1727 (C=O) cm-1; 1H nmr: ꢁ 4.20 (t, 4H,
J = 12.8 Hz), 3.07 (brs, 4H), 2.54 (t, 2H, J=12.8 Hz), 2.23 (s,
6H), 2.18 (brs, 2H), 2.05-2.00 (m, 8H), 1.93-1.89 (m, 4H), 1.56-
1.54 (m, 4H); 13C nmr: ꢁ 175.8(2), 61.3(2), 60.2(4), 40.1(2),
33.1(4), 31.2(2), 27.9, 24.5(4). Anal. Calcd for C21H34N2O4
•2C2H2O4: C, 53.76; H, 6.86; N, 5.03. Found: C, 54.18; H, 7.03;
N, 5.12.
3ꢀ,3ꢂ´-Ethylene glycol bis(tropane-3-carboxylate) (7a).
This compound was isolated as a colorless liquid (17%) and
1
converted into the oxalate salt. ir: 1729 (C=O) cm-1. H nmr: ꢁ
4.26 (brs, 4H), 3.16 (t, 2H, J = 3.2 Hz), 3.07 (t, 2H, J = 3.2 Hz),
2.60-2.51 (m, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 2.20 (dd, 1H, J = 15,
2 Hz), 2.07-2.0 (m, 4H), 1.90-1.83 (m, 4H), 1.63 (ddd, 2H, J = 13,
6.0, 3.5 Hz), 1.57-1.51 (m, 4H); 13C nmr: ꢁ 176.0, 175.4, 62.6 (2),
62.3(2), 60.6, 60.3, 40.5, 40.0, 34.5, 33.4, 33.3(2), 31.5(2),
26.4(2), 24.8(2). Anal. Calcd for C20H32N2O4•2C2H2O4•2H2O: C,
49.65; H, 6.94; N, 4.82. Found: C, 49.93; H, 7.23; N, 4.77.
Ethylene glycol bis(tropane-3ꢂ-carboxylate) (9a). To finely
powdered (8) [14] (1.0 g, 6.0 mmol) in a 50 ml round bottom
flask were added chloroform (10 ml) and thionyl chloride (1.8
ml, 24 mmol). The reaction was refluxed for 3 h under nitrogen.
The solvent was removed under reduced pressure and the
residue was flashed twice with benzene to afford the acid
chloride. Without further purification, the crude product was
added slowly to a vigorously stirred solution of diol (2.4 mmol)
and anhydrous pyridine (3 ml). After complete addition, the
mixture was heated to 110 °C under nitrogen for 16 h. The
mixture was cooled to room temperature and water (10 ml) and
dichloromethane (10 ml) were added to dissolve any solids in
the mixture. The organic layer was separated and the water
phase was extracted with dichloromethane (3 ꢃ 10 ml). The
organic layers were combined, dried (sodium sulfate) and
concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel-dichloromethane: methanol:
triethylamine, 80:2:1, v/v) to afford 620 mg of 9a (71%) as a
white solid. mp 96-98 °C; ir: 1732 (C=O) cm-1; 1H nmr ꢁ 4.21 (s,
4H), 3.17 (t, 4H, J = 3.2Hz), 2.58 (tt, 2H, J = 13, 5.6 Hz), 2.27
(s, 6H), 2.05-2.01 (m, 4H), 1.88 (td, 4H, J = 13, 2.4 Hz), 1.63
(ddd, 4H, J = 13, 5.4, 3.2 Hz), 1.57-1.52 (m, 4H); 13C nmr: ꢁ
175.3(2), 62.3(4), 60.6(2), 40.0(2), 34.6(2), 33.4(4), 26.4(4).
This compound was converted into the oxalate salt. Anal. Calcd
for C20H32N2O4•2C2H2O4: C, 52.94; H, 6.66; N, 5.14. Found: C,
52.82; H, 6.84; N, 4.82.
General Procedure for the Synthesis of Diol bis(tropane-
3ꢂ-carboxylate) (9b-j). To finely powdered (8) [14] (1 equiv.)
in a round bottom flask were added chloroform (52 equiv.) and
thionyl chloride (4 equiv.). The reaction was heated at reflux for
3 h under nitrogen. The solvent was removed under reduced
pressure and the residue was flashed twice with toluene to afford

1430
S. Zhang, S. Izenwasser, D. Wade, J. Cheng, Y. Liu, L, Xu, M. L. Trudell
Vol 44
nmr: ꢀ 175.5(2), 64.3(2), 60.4(4), 39.8(2), 34.4(4), 33.1(2), 28.8,
28.5(2), 26.1(4), 25.7(2). Anal. Calcd for C25H42N2O4
•2C2H2O4•1/2H2O: C, 55.84; H, 7.60; N, 4.49. Found: C, 55.79;
H, 7.61; N, 4.56.
1,8-Octanediol bis(tropane-3ꢁ-carboxylate) (9h). This
compound was isolated as a light brown oil (52%) and converted
into the oxalate salt. 1H nmr: ꢀ 4.04 (t, 4H, J = 13.2 Hz), 3.19
(brs, 4H), 2.62-2.54 (m, 2H), 2.29 (s, 6H), 2.05-2.03 (m, 4H),
1.94-1.87 (m, 4H), 1.67-1.54 (m, 12H), 1.30-1.26 (m, 8H); 13C
nmr: ꢀ 175.6(2), 64.4(2), 60.4(4), 39.8(2), 34.4(4), 33.2(2),
29.1(2), 28.6(2), 26.1(4) 25.8(2). Anal. Calcd for C26H44N2O4•
2C2H2O4: C, 57.31; H, 7.70; N, 4.45. Found: C, 57.75; H, 7.67;
N, 4.49.
n-Butyl 8-methyl-8-azabicyclo[3.2.1]octan-3ꢁ-carboxylic
acid ester (10a). This compound was isolated as a colorless oil
(73%) and converted into the oxalate salt. 1H nmr: ꢀ 4.05 (t, 2H,
J = 13.2Hz), 3.19(brs, 2H), 2.63-2.54(m, 1H), 2.30(s, 3H), 2.05-
2.03(m, 2H), 1.94-1.88(m, 2H), 1.67-1.56(m, 6H), 1.41-1.34(m,
2H), 0.92(t, 3H, J=15.2Hz); 13C nmr: ꢀ 175.6, 64.2, 60.4(2),
39.7, 34.4(2), 33.1, 30.6, 26.1(2), 19.1, 13.6. Anal. Calcd for
C13H23NO2 . C2H2O4 .1/2 H2O: C, 55.53; H, 8.08; N, 4.32. Found:
C, 55.21; H, 8.08; N, 4.21.
n-Decyl 8-methyl-8-azabicyclo[3,2,1]octan-3ꢁ-carboxylic
acid ester (10b). This compound was isolated as a colorless oil
(74%) and converted into the oxalate salt. 1H nmr: ꢀ 4.03 (t, 2H,
J = 13.2Hz), 3.20-3.19(m, 2H), 2.62-2.54(m, 1H), 2.30(s, 3H),
2.06-2.02(m, 2H), 1.95-1.88(m, 2H), 1.67-1.54(m, 6H),
1.26(brs, 14H), 0.88(t, 3H, J=13.6Hz); 13C nmr: ꢀ 175.6, 64.5,
60.4(2), 39.7, 34.4(2), 33.1, 31.8, 29.3, 29.2(2), 28.6, 26.1(2),
25.9, 22.6, 15.9, 14.1. Anal. Calcd for C19H35NO2 •2HCl
•1/2H2O: C, 64.27; H, 10.50; N, 3.95. Found: C, 63.81; H,
10.47; N, 3.90.
1,9-Nonanediol bis(tropane-3ꢁ-carboxylate) (9i). This
compound was isolated as a light brown oil (86%) and converted
1
into the oxalate salt. H nmr: ꢀ 4.04 (t, 4H, J = 14.0 Hz), 3.24
(brs, 4H), 2.62-2.55 (m, 2H), 2.33 (s, 6H), 2.08-2.06 (m, 4H),
1.98-1.92 (m, 4H), 1.69-1.56 (m, 12H), 1.29 (brs, 10H); 13C
nmr: ꢀ 175.2(2), 64.3(2), 60.4(4), 39.5(2), 34.1(4), 32.8(2), 29.1,
28.9(2), 28.4(2), 25.9(1), 25.6(2). Anal. Calcd for C27H46N2O4•
2C2H2O4: C, 57.93; H, 7.84; N, 4.36. Found: C, 57.95; H, 7.81;
N, 4.51.
Acknowledgment. The authors are grateful to the National
Institute on Drug Abuse for the financial support of this
research.
1,10-Decanediol bis(tropane-3ꢁ-carboxylate) (9j). This
compound was isolated as a light brown oil (74%) and converted
into the oxalate salt. 1H nmr: ꢀ 4.04 (t, 4H, J = 13.6 Hz), 3.19
(brs, 4H), 2.62-2.53 (m, 2H), 2.29 (s, 6H), 2.06-2.02 (m, 4H),
1.94-1.87 (m, 4H), 1.68-1.54 (m, 12H), 1.28-1.27 (m, 12H); 13C
nmr: ꢀ 175.6(2), 64.4(2), 60.4(4), 39.8(2), 34.4(4), 33.2(2),
29.4(2), 29.2(2), 28.6(2), 26.1(4), 25.8(2). Anal. Calcd for
C28H48N2O4•2C2H2O4•1/2H2O: C, 57.31; H, 7.70; N, 4.45.
Found: C, 57.75; H, 7.67; N, 4.49.
REFERENCES AND NOTES
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General Procedure for the Synthesis of tropane-3ꢁ-
carboxylate esters. To finely powdered (8) [14] (1 equiv.) in a
round bottom flask were added chloroform (52 equiv.) and
thionyl chloride (4 equiv.). The reaction was heated at reflux for
3 h under nitrogen. The solvent was removed under reduced
pressure and the residue was flashed twice with toluene to afford
the acid chloride. Without further purification, the crude acid
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(10%) to a vigorously stirred solution of alcohol (1.2 equiv.) and
anhydrous pyridine (10 equiv.). After complete addition, the
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layer was separated and the aqueous phase was extracted with
dichloromethane. The organic layers were combined, dried
(sodium sulfate) and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel-
dichloromethane: methanol: triethylamine, 80:2:1, v/v) to afford
10a-b as an oil. The ir and nmr spectra were recorded for the
freebase. The freebase was converted into the oxalate salt for
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