Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters

Article abstract of DOI:10.1021/jm0101242

Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). Inhibition of the DAT causes an increase of dopamine in the synapse with a resultant activation of postsynaptic receptors. The rapid onset and short duration of action of cocaine contribute to its high addictive potential. Consequently, the design of tropane analogues of cocaine that display longer onset times on the DAT and extended duration of action is driven by the need to develop cocaine medication. This study extends the exploration of bridge hydroxylated azabicyclo[3.2.1] octanes (tropanes). A series of 6- and 7-hydroxylated tropanes was prepared and evaluated biologically. Structure activity relationships lead to the following conclusions. Bridge hydroxylated tropanes retain biological enantioselectivity but display higher DAT versus SERT selectivity, particularly for the 3α-aryl compounds as compared with the 3β-aryl compounds, than the bridge unsubstituted analogues. The 7-hydroxyl compounds are more potent at the DAT than their 6-hydroxyl counterparts. The general SAR of the tropanes is maintained and the rank order of potencies based on substitution at the C3 position remains 3,4-dichloro > 2-naphthyl > 4-fluoro > phenyl.

Full text of DOI:10.1021/jm0101242

J . Med. Chem. 2001, 44, 2619-2635
2619
Syn th esis of 6- a n d 7- Hyd r oxy-8-a za bicyclo[3.2.1]octa n es a n d Th eir Bin d in g
Affin ity for th e Dop a m in e a n d Ser oton in Tr a n sp or ter s†
Peter C. Meltzer,*,‡ Bing Wang,‡ Zhengming Chen,‡ Paul Blundell,‡ Muthusamy J ayaraman,‡
Mario D. Gonzalez,‡ Clifford George,§ and Bertha K. Madras|,#
Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, Naval Research Laboratory, Washington, D. C. 20375, and
Department of Psychiatry, Harvard Medical School and New England Regional Primate Center,
Southborough, Massachusetts 01772
Received March 19, 2001
Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant
effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT).
Inhibition of the DAT causes an increase of dopamine in the synapse with a resultant activation
of postsynaptic receptors. The rapid onset and short duration of action of cocaine contribute to
its high addictive potential. Consequently, the design of tropane analogues of cocaine that
display longer onset times on the DAT and extended duration of action is driven by the need
to develop cocaine medication. This study extends the exploration of bridge hydroxylated
azabicyclo[3.2.1]octanes (tropanes). A series of 6- and 7-hydroxylated tropanes was prepared
and evaluated biologically. Structure activity relationships lead to the following conclusions.
Bridge hydroxylated tropanes retain biological enantioselectivity but display higher DAT versus
SERT selectivity, particularly for the 3R-aryl compounds as compared with the 3â-aryl
compounds, than the bridge unsubstituted analogues. The 7-hydroxyl compounds are more
potent at the DAT than their 6-hydroxyl counterparts. The general SAR of the tropanes is
maintained and the rank order of potencies based on substitution at the C3 position remains
3,4-dichloro > 2-naphthyl > 4-fluoro > phenyl.
In tr od u ction
It is interesting that activation of postsynaptic recep-
tors does not appear to be sufficient to lead to addiction.
Rather, it is the rapid onset and short duration of action
of cocaine and concomitant surge in available dopamine
that presumably accounts for the rapid cycles observed
clinically and the high addiction potential of cocaine.15
Consequently, much research has addressed the design
and synthesis of molecules that would moderate the
kinetics of onset of action and extend duration of
action.9,15,16 In this fashion, a cocaine replacement may
be envisaged in which the stimulatory characteristics
of cocaine are attenuated by expeditious control of
pharmacokinetics. This approach is analogous to the
behavioral and kinetic profile of methadone used to treat
opiate addiction.17
Cocaine is a potent stimulant of the central nervous
system. While the exact mechanism of action of cocaine
is as yet uncertain, it is known that the dopamine
transporter (DAT) plays a primary role in its biological
activity. Its reinforcing and stimulant effects are thought
to be related to its ability to bind to and inhibit the
dopamine transporter.1-8 Inhibition of the transporter
causes an increase of the concentration of the neuro-
transmitter dopamine (DA) in the synapse, with a
resultant increase in activation of postsynaptic recep-
tors.9 Several classes of compounds are under active
investigation as medications for cocaine addiction.
Among the candidates are molecules that serve as
cocaine antagonists or replacements. A clinically useful
cocaine antagonist would inhibit the binding of cocaine
to the transporter while allowing free passage of the
neurotransmitter itself and thus its reuptake into the
presynaptic cell.10,11 Such a “dopamine sparing cocaine
antagonist”12 has been the focus of much research13,14
since it would likely provide a novel route to treating
cocaine addiction. To date, such a dopamine sparing
cocaine antagonist has not been identified. Another class
of compounds are dopamine transport inhibitors with
a different pharmacokinetic profile than cocaine.
Our search for such compounds has included a variety
of tropane analogues in which the 8-aza moiety of the
prototypic phenyltropane, WIN 35,428 (Figure 1) has
been substituted by both oxygen (2â-carbomethoxy-3â-
(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane)18,19 and
carbon (2â-carbomethoxy-3â-(3,4-dichlorophenyl)-bicyclo-
[3.2.1]octane).20 These 8-substitutions have been pur-
sued to examine the significance of moieties capable of
hydrogen bonding to a residue (Asp79 12
acceptor site of the biomacromolecule.
)
within the
To explore the effect of altered nucleophilicity of an
8-aza substituent on DAT function, we introduced
hydroxyl groups at both the 6- and 7-bridge positions
of selected 8-azabicyclo[3.2.1]octanes. We investigated
this series despite the fact that the bridge area may be
sensitive to increased steric bulk. In this regard, DAT
affinities were reduced by homologation of the bridge
by introduction of a carbon in a [3.3.1] homotropane,21
† A preliminary communication of this work was published in
Tetrahedron Lett. 1997, 38, 1121-1124.
* Corresponding author: Dr. Peter C. Meltzer, Organix Inc., 240
Salem Street, Woburn, Massachusetts, 01801. Tel: 781-932-4142.
Fax: 781-933-6695. E-mail: Meltzer@organixinc.com.
| Corresponding author, biology.
‡ Organix Inc.
§ Naval Research Laboratory.
#
Harvard Medical School and New England Regional Primate
Center.
10.1021/jm0101242 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/30/2001

2620 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
F igu r e 1. Structures of Lead Bicyclo[3.2.1]octanes
by the presence of 6-alkyl groups,22 and by the introduc-
tion of a methoxyl group at either the 6- or 7-position
of cocaine.23
bridgehead proton at C1 or C5, respectively. This
therefore confirms the â-orientation of the hydroxy
moieties in 1a and 1b. No R-hydroxy isomers were
isolated.
In contrast, certain “back-bridged” compounds proved
quite potent at the DAT.24 Both 6- and 7-hydroxy groups
in cocaine have been reported, but without biological
data.25 Our rationale for exploration of bridge hydroxy-
lated 3-aryltropanes was that a â-oriented hydroxyl
group might establish intramolecular hydrogen bonding
to the 8-nitrogen and thus reduce its nucleophilicity. In
1997, we published a preliminary study in which we
described the synthesis of the racemic parent com-
pounds 2â-carbomethoxy-3â-(3,4-dichlorophenyl)-7â-hy-
droxy-8-methyl-8-azabicyclo[3.2.1]octane and 2â-carbo-
methoxy-3â-(3,4-dichlorophenyl)-6â-hydroxy-8-methyl-
8-azabicyclo[3.2.1]octane (Figure 1).26,27 Subsequently,
two bridge hydroxylated 3-tolyltropanes were shown to
have nanomolar potency for DAT inhibition.28,29 We now
report the feasibility of producing extremely potent and
selective DAT inhibitors via this modification of phenyl-
tropanes.
Ch em istr y. The route of synthesis is shown in
Schemes 1-3. The 6- and 7-hydroxy target compounds
were obtained individually; however, for ease of pre-
sentation, the position of bridge substitution is not
specified in the schemes. The 6- and 7-hydroxy â-keto
esters 1a and 1b were prepared as described previ-
ously.26,30-32 The stereochemistry of the â-hydroxyl
group at C6 (1a ) or C7 (1b) was confirmed by NMR
studies. Most important, a coupling constant of J ) 0
Hz between H-5 and H-6 (δ ) 4.05 ppm) in the case of
1a , and between H-1 and H-7 (δ ) 4.1 ppm) in the case
of 1b, confirmed a dihedral angle of 90° for both
compounds. This dihedral angle can only be obtained
between a 6R- or 7R-oriented proton and the relevant
A mixture of 6- and 7-hydroxy-â-keto esters 1a and
1b was methoxymethylated with dimethoxymethane in
dichloromethane with p-toluenesulfonic acid as catalyst.
Column chromatography provided regioisomers 2a and
2b which were individually utilized, as described below.
1
The H NMR spectra of 2a and 2b, as well as pure 1a
and 1b, proved quite interesting. Both compounds 1a
and 2a clearly exhibit the expected20 equilibrium dis-
tribution between the 2R-carboxy ester, enol-2-carboxy
ester, and 2â-carboxy ester with the result that their
1H NMR spectra are quite complex. Compounds 1b and
2b surprisingly do not. In fact, in CDCl3 solution,
compounds 1b and 2b exist exclusively as the enol.
Unequivocal evidence for this lies (as exemplified for
1b) in the complete absence of a C2 proton and the
presence of a doublet at δ 1.73 (H4â: J ) 18.6 Hz) and
a double doublet at δ 2.76 (H4R: J ) 18.6 and 4.7 Hz)
integrating for fully one proton each. The enolic proton
at δ 11.8 also fully integrates for one proton. The reason
for this preference for the enol in the 7-substituted
compounds is unclear.
Conversion of 2 to the vinyl enoltriflates 3 was
achieved with sodium bis(trimethylsilyl)amide and N-
phenyltrifluoromethanesulfonimide at low tempera-
ture.33 The alkenes 4 and 5 were then obtained in good
yield by Suzuki coupling34 of the triflates 3 with the
corresponding boronic acids. Reduction of 4 and 5
(Scheme 2) with samarium iodide at -78 °C then
afforded the saturated tropane analogues 9-12.33 Com-
1
pounds 9 and 11 were shown by H NMR to exist in a
chair conformation, and 10 and 12 assumed a boat

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2621
Sch em e 1. Synthetic Route to 2,3-Unsaturated Tropanesa
a
Reagents: (i) H2NCH3; (ii) CH2(OCH3)2, pTSA; (iii) NaN(TMS)2, PhNTf2; (iv) Pd2(dba)3, ArB(OH)2; (v) TMSBr.
Sch em e 2. Synthetic Route to Bridge Oxygenated Tropanesa
a
Reagents: (i) SmI2; (ii) TMSBr, CH2Cl2; (iii) N-CH3-morpholine-N-oxide, tetra-n-propylammoniumperruthenate.
conformation. Finally, the MOM groups of each of 4, 5
and 9-12 were removed in high yield with trimethyl-
silyl bromide in methylene chloride at 0 °C to give the
corresponding hydroxy tropanes 7 and 8 (Scheme 1), 14
and 15, and 17 and 18 (Scheme 2), respectively.
The 7-ketoesters 19 and 20 were obtained in good
yield upon oxidation of 15 and 18, respectively, with
tetra-n-propylammonium perruthenate35 and N-methyl-
morpholine-N-oxide in methylene chloride.
Thus 11a was reacted with N,O-dimethylhydroxylamine
and trimethyl aluminum in methylene chloride to
provide the Weinreb amide 21 in high yield. Treatment
with ethylmagnesium bromide in THF37 then provided
the ethyl ketone 22 quantitatively. Deprotection with
TMSBr yielded the target compound 23. The 3R-aryl
analogue 26 was obtained similarly from 12a via 24 and
25.
To determine the biological enantioselectivity of these
hydroxytropanes, six enantiopure 7â-hydroxy-3-(3,4-
dichlorophenyl) analogues were prepared. While we and
The 2-ethyl ketone analogues 23 and 26 were pre-
pared (Scheme 3) via an intermediate Weinreb amide.36

2622 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
Ta ble 1. Physical Data for Six Enantiopure Analogues
Sch em e 3. Synthetic Route to Bridge Oxygenated
2-Keto Tropanesa
compound
mp °C
X-raya
[R]2D1
(1R)-8a
129.0-131.0
186.0-187.0
149.0-150.0
130.4-132.4
185.5-186.5
148.5-150.0
(1R)
+57°
-26°
+47°
-58°
+25°
-48°
(1R)-15a
(1R)-18a
(1S)-8a
(1S)-15a
(1S)-18a
(1R)
(1S)
a
X-ray crystallographic analysis confirmed stereochemical as-
signments.
keto ester 2b was reacted with (1′S)-(-)-camphanic
chloride to obtain a mixture of diastereomers that could
not be separated by column chromatography. Multiple
recrystallizations yielded a sufficient amount of the
(1R,1′S) diastereomer 27 only. Pure (1S,1′S) diastereo-
mer could not be obtained by these means. Hydrolysis
of (1R)-27 with lithium hydroxide then provided enan-
tiopure keto ester (1R)-2. This keto ester was then
taken through the same synthetic pathway as shown
for racemates 1b (Schemes 1 and 2) to obtain the
enantiopure (1R)-8a , (1R)-15a , and (1R)-18a .
This approach provided only the 1R-tropanes. There-
fore, an alternate approach was also developed. (Scheme
4). The racemic 2,3-ene 8a was esterified with (1′S)-
(-)-camphanic chloride to obtain a diastereomeric mix-
ture 28 which was purified by column chromatography
to obtain (1S,1′S)-28. Hydrolysis with LiOH then
provided the enantiopure target compound (1S)-8a
which was reduced with SmI2 to obtain the 3â (1S)-
15a and 3R (1S)-18a target compounds. Physical data
relating to these six compounds are presented in Table
1. Each enantiomeric pair had equal and opposite optical
rotations. Since this is an unreliable measure of enan-
tiomeric excess, an NMR method was developed. Each
of the six compounds was obtained in >98% ee as
a
Reagents: (i) HN(CH3)OCH3 Al(CH3)3; (ii) ETMgBR; (iii)
TMSBR, CH2Cl2.
others38-40 have had substantial success in recrystalli-
zation of diastereomeric tartrate salts of keto esters such
as 1b, we were unable to obtain material of satisfactory
enantiomeric excess (ee) with the bridge hydroxyl group
present. We therefore elaborated two resolution routes,
both of which relied upon the establishment of diaster-
eomeric camphanate esters (Scheme 4). The routes had
the added advantage of allowing quantification of ee by
1H NMR analysis (vide infra). Thus, the MOM protected
1
confirmed by H NMR. In this regard, NMR spectra of
the camphanate esters are unequivocal since one of the
camphanate methyl resonances for the (1R,1′S) and
(1S,1′S) compounds is baseline separated and can
therefore be quantified reliably. Thus, the (1R)-27
Sch em e 4. Resolution of 8A, 15A, and 18Aa

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2623
Sch em e 6. Synthesis of Diarylmethoxy Tropanesa
Sch em e 5. Inversion at C6 and C7a
a
Reagents: (i) NaBH4; (ii) 4,4’-difluorobenzhydrol, pTSA.
a
Reagents: (i) C6H5COOH, Ph3P, DEAD; (ii) LiOH, THF.
manifests a methyl group at δ 0.99. The (1S)-27 shows
the same methyl at δ 1.02. Absolute stereochemistry
was assigned by X-ray crystallographic analysis for
(1R)-8a , (1R)-18a , and (1S)-18a . This allowed confident
stereochemical assignment of the remaining compounds.
It should be noted that the designation of chirality
for these bridge-hydroxylated tropanes is reversed from
that of the bridge unsubstituted parent compounds. This
is a result of the rules for nomenclature and does not
reflect a difference in absolute stereochemistry. Thus
the more potent enantiomers here are the 1S designated
compounds in contrast to the 1R active enantiomers of
the parent compounds 6a , 13a , or 16a .
Inversion of the bridge hydroxyl group in 17a and 18a
was effected (Scheme 5) in two steps by straightforward
Mitsunobu chemistry.41 Thus, the 6â-hydroxy 17a was
reacted with benzoic acid and triphenylphosphine in the
presence of diethylazodicarboxylate to give 29a . The
benzoyl group was then removed with LiOH/THF to
provide the 6R-hydroxy analogue 30a . The 7â-hydroxy
analogue 18a was treated similarly to obtain 30b.
The 1H NMR spectra of these inverted compounds are
interesting in that the R-oriented hydroxyls have a
surprisingly large through space compression effect on
the axial protons at H2R in the case of the 7-OH
compound 30b and at H4R in the case of the 6R-hydroxy
compound 30a . Such effects have been observed previ-
ously in epibatidine analogues.42 Boat versus chair
conformation of bicyclo[3.2.1]octanes has always been
assigned on the basis of 1H NMR, and the signal
corresponding to H4R in 2â-substituted-3R-arylbicyclo-
[3.2.1]octanes has been particularly diagnostic. It gener-
ally appears as a double double doublet at δ 1.3 showing
large geminal coupling interactions with H4â (ca. 14 Hz)
and H3 (trans-diaxial coupling ca. 11 Hz) and a small
coupling constant with H5 (ca. 2 Hz). That is the case
for the 2â-carbomethoxy-3R-(3,4-dichlorophenyl) hy-
droxylated derivatives when the hydroxyl group is in
the 6â (17a ), 7â (18a ), or 7R (30b) orientation (in the
latter case obscured by the presence of a signal corre-
sponding to H6â). In the case of the 6R-hydroxy deriva-
tive 30a , the signal corresponding to H4R was observed
at δ 2.15 (∆ ) 0.85 ppm) (with the appropriate multi-
plicity described above) due to the strong 1,4-diaxial
F igu r e 2. Absolute Configurations of (1R)-8a , (1R)-18a , (1S)-
18a
interaction with the 6R-OH. A similar displacement (∆
) 0.9 ppm) was observed in the signal corresponding
to H2R in the 7R-hydroxy compound, 30b. Finally the
1H NMR spectrum of the 7-keto compound 20 showed
a strong resemblance with the hydroxy analog’s spectra,
although the signal corresponding to H4R appeared at
lower fields (δ 1.51) and the trans-diaxial coupling
interactions H3-H2 and H3-H4R were slightly weaker
than expected (J ) 8 Hz). These minor differences
indicate a pseudo boat conformation.
The diarylmethoxy compounds (Scheme 6) 32a and
32b were obtained from the MOM protected keto esters
1a and 1b. Reduction with sodium borohydride gave the
3R-hydroxy compounds 31. Subsequent reaction with
4,4′-difluorobenzhydrol in methylene chloride with p-
toluenesulfonic acid provided 32a or 32b directly.
To assign absolute stereochemistry for those com-
pounds that were prepared in enantiomerically pure
form, X-ray structural analyses were conducted. Com-
pounds (1R)-8a , (1R)-18a , and (1S)-18a were recrystal-
lized from methylene chloride/pentane to obtain suitable
crystals. Compound (1S)-18a was thus demonstrated
to be the 1S-enantiomer. Compound (1R)-18a was
proved to be 1R, and compound (1R)-8a , the precursor
to (1R)-18a , was likewise confirmed as 1R (Figure 2).
A comparison of the conformation established by 1H

2624 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
Ta ble 2. Inhibition of [3H]WIN 35,428 Binding to the Dopamine Transporter and [3H]Citalopram Binding to the Serotonin
Transporter in Rhesus (Macaca mulatta) or Cynomolgus Monkey (Macaca fasicularis) Caudate-Putamena
IC50 (nM)
SERT
IC50 (nM)
SERT
IC50 (nM)
SERT
SERT/
DAT
SERT/
DAT
SERT/
DAT
R1
compound
DAT
compound
DAT
compound
DAT
H
6a , O-1109 1.16
867
747
60
13a , O-401 (R) 1.09 2.47
2
16a , O-1157 (R) 0.38 27.7
73
6-OH 7a , O-1591 55.1
7-OH 8a , O-1813 19.4
7-OH (1R)-8a ,
3320
>6000
1590
14a , O-1299
3.02 166
1.42 27.7
2,690 139
55
20
0.05
17a , O-1926
18a , O-1163
(1R)-18a ,
O-1676
6.09 1450
1.19 1390
482 5300
238
1170
11
>300 15a , O-1164
6
265
(1R)-15a ,
O-1675
O-1677
7-OH (1S)-8a ,
O-1923
7.37
5370
730
(1S)-15a ,
O-1945
0.3
15
50
(1S)-18a ,
O-1924
0.76 1220
1610
H
6b, O-1173 2.94
109
260
677
7990
37
1
15
20
13b, O-1229 (R) 0.49 2.19
5
4
4
15
16b, O-1228
17b, O-1748
18b, O-1952
16c, O-1204
0.57 5.95
10
6
34
63
6-OH 7b, O-1627 246
7-OH 8b, O-1815 45
H
14b, O-1814
15b, O-1981
13c, O-381
(WIN)
7.7
1.26 5.57
11.0 160
34.2
32
2.8
180
94
6c, O-1104 408
17.9 1,130
6-OH 7c, O-1588 >20 000 >20 000
1
1
11
1
1
14c, O-1817
15c, O-1983
13d
14d , O-1816
15d , O-1953
477
123
65
6150 88 000
235
>20 000 >42
17c, O-1755
18c, O-1951
16d
17d , O-1589
18d , O-1954
739 5820
110 >20 000 >120
NA NA
3530 >10 000 >3
518 >100 000 >190
8
7-OH 8c, O-1927 7730
6d , O-1449 2590
>10 000
>10 000 >80
H
28 600
NA
-
6-OH 7d , O-1644 >150 000 >100 000
7-OH 8d , O-1944 >10 000 >10 000
14
>10 000 >43
a
Each value is the mean of two or more independent experiments each conducted in different brains and in triplicate. Errors generally
do not exceed 15% between replicate experiments. Highest doses tested were generally 10-100 µM.
NMR studies in solution (CDCl3) with that evident in
the solid state as evidenced by X-ray crystallography
proved interesting. While both 3R-aryl enantiomers
adopted a boat conformation in solution, the 1R enan-
tiomer (1R)-18a presented in chair conformation in the
solid state. Among the numerous X-ray crystallographic
structural determinations that we have conducted on
tropanes, (1R)-18a represents the first instance in
which the conformation in the solid state is markedly
different from that in solution. This is highly unlikely
to be a consequence of enantiomeric differences ((1R)-
18a vs (1S)-18a ). However, this difference is potentially
important since a chair conformation would place the
3R-aryl substituent in an axial position. SAR studies
have taken into consideration that a 3â-substituent,
which favors the chair conformation of the bicyclo[3.2.1]-
octane system, places the 3-aryl group in an equatorial
position. Further, the 3R-aryl compounds have, on the
basis of NMR studies and all prior X-ray studies, been
shown to adopt a boat conformation in which the C3-
aryl group is again oriented equatorially. This contrast
between the crystal conformation of (1S)-18a (boat) as
compared with that of its enantiomer (1R)-18a (chair)
is probably fortuitous. It was noted that the unit cell
structures for (1R)-18a and (1S)-18a differed with
respect to intermolecular hydrogen bonding. It appeared
that (1S)-18a manifested H-bonding between the 7-OH
and the 7-OH of an adjacent molecule, while (1R)-18a
manifested H-bonding between a 7-OH and an 8-N of
conformation of the 3R-molecule (1S)-18a in CDCl3
solution is pseudo-boat (evidenced by the double double
doublet resonances for H4R at δ 1.24). It maintains this
conformation in CD3OD/D2O (H4R: ddd at δ 1.3) or CD3-
OD/H2O (H4R: ddd at δ 1.3) under a water suppression
protocol. Therefore intermolecular hydrogen bonding
does not favor chair conformation over the boat for this
compound. This result highlights the caution that
should be exercised as one extrapolates from a three-
dimensional crystal structure to a putative three-
dimensional structure within the biological system.
Biology. The affinities (IC50) for the dopamine and
serotonin transporters were determined in competition
studies. The dopamine transporter was labeled with [3H]-
3â-(4-fluorophenyl)tropane-2â-carboxylic acid methyl
ester ([3H]WIN 35,428 or [3H]CFT (1 nM)) and nonspe-
cific binding was measured with (-)-cocaine (30 µM).6
[3H]Citalopram was used to label the serotonin trans-
porter and nonspecific binding was measured with
fluoxetine(10 µM).18 Binding data for the 2-carbomethoxy-
6- or 7-hydroxy compounds are presented in Table 2.
Table 3 presents binding data for the 7-keto, 6R- and
7R-hydroxy, and 3-diarylmethoxy compounds. Studies
were conducted in monkey striatum because this tis-
sue27 is used in an ongoing investigation of structure
activity relationships at the DAT, and meaningful
comparisons with an extensive database can be made.
Competition studies were conducted with a fixed con-
centration of radioligand and a range of concentrations
of the test drug. All drugs inhibited [3H]WIN 35,428 and
[3H]citalopram binding in a concentration-dependent
manner.
1
an adjacent molecule. H NMR experiments were con-
ducted to examine the possible influence of such inter-
molecular hydrogen bonding upon conformation. The

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2625
Ta ble 3. Inhibition of [3H]WIN 35,428 Binding to the
Dopamine Transporter and [3H]Citalopram Binding to the
Serotonin Transporter in Rhesus or Cynomolgus Monkey
Caudate-Putamenc
bicyclo[3.2.1]octane series,19,27 we have learned that to
achieve high potency and selectivity, an optimum
template should be used as a starting point. We have
therefore generally elected to prepare derivatives of the
3,4-dichlorophenyl substituted template, since this sub-
stitution, and to a similar extent the 2-naphthyl sub-
stitution,46 have provided among the most potent DAT
inhibitors. Furthermore, SAR studies have clearly dem-
onstrated that selectivity of binding to the DAT versus
binding to the SERT can be obtained in the 3R-aryl as
well as the 2,3-unsaturated series of compounds.27 For
these reasons, the compounds shown in Tables 2 and 3
were prepared.
IC50 (nM)
IC50 (nM)
DAT SERT
compd
DAT SERT
compd
19
20
23
26
O-2097 14.1 290
O-2096 14.2 7038
O-2074 0.81 97
30b O-2032 3.04
32a O-2070 448
32b O-2031 6300
33a O-2016 48
991
4850
9560
533
O-2099 1.1
2520
30a O-2015 33.2 10700 34b O-1754 32 600 >20 000
In tr od u ction of 6- or 7-Br id ge Hyd r oxyl Gr ou p s.
Table 2 presents the 6- and 7-hydroxylated compounds
as well as the bridge unsubstituted (R1 ) H) parent
compounds for comparison. In general, the 7-hydroxy
compounds (8, 15, 18) are more potent than the 6-hy-
droxy compounds (7, 14, 17). However, in a comparison
of the 2,3-unsaturated racemates, 6a with 7a and 8a ,
it is clear that the unsubstituted compound 6a is
significantly more potent than either 7a or 8a . When
only active enantiomers are compared, it is apparent
that the hydroxylated analogues are of comparable
potencies to the bridge unsubstituted compounds. Com-
pound (1R)-13a exhibits DAT IC50 ) 1.09 nM while the
active (1S)-15a is about three times more potent (0.3
nM) and 25-fold more selective than 13a (Table 3).
When the aromatic ring is oriented in the 3R-configu-
ration, the parent-unsubstituted compound (1R)-16a
has DAT IC50 ) 0.38 nM and the hydroxylated enan-
tiopure compound (1S)-18a shows a similar value of
0.76 nM. In this case, the hydroxylated compound shows
a selectivity ratio of 1610 and is therefore 22-fold more
selective than 16a . However, (1S)-18a is 32-fold more
selective than (1S)-15a thus demonstrating the en-
hanced selectivity of 3R-configured compounds over
their 3â-counterparts. Thus, introduction of an hydroxyl
at C7 has, at least, maintained potency of DAT inhibi-
tion and retained or may have increased selectivity
versus inhibition of the SERT. This increase in selectiv-
ity is evident in the 6-hydroxy compounds 14a and 17a
as well. The fact that the 1R configured compounds
(1R)-8a , (1R)-15a , and (1R)-18a are considerably less
potent than the 1S enantiomers points, once again, to
the biological enantioselectivity of the DAT and SERT.
c Each value is the mean of two or more independent experiments
each conducted in different brains and triplicate. Errors generally
do not exceed 15% between replicate experiments. Highest doses
tested were generally 10-100 µM.
Discu ssion
In the search for cocaine medications, it has not been
established that more potent inhibitors of the DAT may
provide more pharmacologically useful compounds.
Therefore, a focus of much of the work in this area has
been to design compounds that range in their affinity
for the dopamine transporter. The bridge-hydroxylated
compounds of this study provide a broad array of
molecules some of which bind with very high affinity
and others that prove much weaker. This family there-
fore provides a testing ground for the role of affinity
upon cocaine medications development. Selectivity for
inhibition of the DAT versus the serotonin transporter
(SERT) is another property of tropanes of considerable
relevance for development of medications and for probes
useful to image the DAT in living brain. It is reasonable
to aspire to high DAT:SERT selectivity for DAT imaging
agents. For cocaine medications, however, the advan-
tages and disadvantages of selectivity are not fully
resolved. Even though the parent compound cocaine is
relatively nonselective for all three monoamine trans-
porters, and an abundance of evidence suggests that
DAT blockade is a significant contributor to the rein-
forcing effects of cocaine, self-administration is sus-
tained in DAT knockout mice.43 One possible interpre-
tation of these findings is that cocaine blocks transport
of dopamine via other transporters in brain regions
critical to maintaining self-administration.44 At a prac-
tical level, these findings would imply that compounds
both selective and nonselective for the DAT should be
assessed in screening programs for cocaine medications.
Within this series of compounds now described, we
discovered that it is feasible to design bridge-substituted
tropanes with either a high or low degree of DAT:SERT
selectivity.
In summary, three conclusions may be reached. First,
the bridge hydroxylated compounds confirm biological
enantioselectivity. Second, the 7-hydroxylated com-
pounds are more potent at the DAT than their 6-hy-
droxyl counterparts. Third, the bridge hydroxylated
compounds are more selective DAT inhibitors than the
unsubstituted analogues.
Effect of Su bstitu tion on th e C3 Ar yl Rin g. The
effects of substitution on the C3-aryl ring of the bridge
hydroxylated compounds in Table 2 mimic other tropane
series27,47 including the 8-oxa19 and 8-carba20 com-
pounds. Thus, for substituents on the C3-position, the
potency for inhibition of the DAT decreases from 3,4-
dichlorophenyl > 3-(2-naphthyl)> 3-fluorophenyl >
phenyl. Further, selectivity for inhibition of the DAT
versus the SERT is greater for those compounds bearing
a 3R-aryl substituent as compared with a 3â-aryl
substituent. The 2,3-unsaturated analogues generally
Introduction of functionality at the 6,7-bridge of
3-phenyltropanes has attracted the attention of a num-
ber of research groups.21-23,26,45 In general, steric bulk
at either position has reduced the affinity of these
compounds for the dopamine transporter. Simple intro-
duction of an hydroxyl group on a 3-aryl tropane is also
not sufficient to provide potent DAT inhibitors.28 Upon
the basis of the SAR that we have uncovered in other

2626 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
display the same rank order of potency at the DAT. They
manifest good selectivity, particularly for those com-
pounds that are potent inhibitors. Thus for both 6- and
7-hydroxylated compounds, 3,4-dichloro substitution
provides similar or slightly higher potency at the DAT
than for introduction of a C3-(2-naphthyl) group. Both
are significantly superior to a 4-fluoro group which, in
turn, is more potent than the unsubstituted phenyl ring
compound. In the 7-hydroxy series, the racemic 3â-
configured 3,4-dichloro compound 15a manifests a DAT
IC50 of 1.42 nM as compared with 1.26 nM for the
2-naphthyl 15b, 123 nM for the 4-fluoro 15c, and 235
nM for the unsubstituted 15d . A similar relationship
is seen in the 3R-configured series: 18a (3,4-dichloro)
> 18b (2-naphthyl) > 18c (4-fluoro) > 18d (H) and the
2,3-enes: 8a (3,4-dichloro) > 8b (2-naphthyl) > 8c (4-
fluoro) > 8d (H). Interestingly, either 6- or 7-hydroxy
substituents reduce affinity of 4-fluoro substitution. The
6â-hydroxy compounds present identical SAR at C3. In
striking contrast to the exciting DAT inhibitor (1S)-
difluoropine40 (DAT IC50 ) 10.9 nM; SERT IC50 ) 3530
nM) the (1R/S)-difluorodiarylmethoxy analogues 32a
(6â-OH) and 32b (7â-OH) (Table 3) manifest high
nanomolar to micromolar affinity for the DAT and
SERT.
in the range of 265-2690 nM. Selectivities for DAT
versus SERT inhibition follow similarly. Thus, the less
active 1R-enantiomer series of the 3,4-dichlorophenyl
analogue manifests selectivities that range from 0.05
to 11-fold ((1R)-8a , (1R)-15a , and (1R)-18a ). In con-
trast, the active 1S-enantiomers show clear differences
in selectivity (50-1610 for (1S)-15a , (1S)-8a , and (1S)-
18a ).
Clearly, biological enantioselectivity is conserved for
bridge hydroxylated tropanes.
Ster eoch em istr y a t C2 a n d C7. It is interesting
that although the 7â-hydroxy-C2R-methylester 33 is
markedly less potent (Table 3) at both the DAT (IC50
)
48 nM) and the SERT (IC50 ) 533 nM) than the C2â
analogue 15a (DAT: 1.42 nM; SERT: 27.7 nM) it is still
almost twice as potent as cocaine at the DAT. In the
absence of ring substitution, as in 34, the 6-hydroxy-
C2R-compound is inactive.
Replacement of the C2 ester with a C2 ethyl ketone
leads to quite potent inhibitors (Table 3). Thus, 23
manifests a DAT IC50 ) 0.81 nM and a SERT IC50 ) 97
nM. As may be anticipated, when a C2 ethyl ketone is
present in a 3R-3,4-dichlorophenyl analogue, as in 26,
one of the most selective and potent DAT inhibitors is
discovered (DAT: 1.1 nM; SERT: 2520 nM) (see Scheme
3).
Selectivity for inhibition of the DAT versus the SERT
is likewise very similar to that evidenced in all other
series.19,20,27 The parent compounds in which no bridge
hydroxylation is present (6, 13, 16) model the series
(Table 2): 2,3-ene (6a ) > 3R (16a ) > 3â (13a ). Thus,
the 3â configured compounds are generally least selec-
tive, and the 2,3-ene and 3R-compounds are more
selective. This difference in selectivity diminishes where
compounds are intrinsically less potent DAT inhibitors.
An example of this is evident in the comparison between
the potent 3,4-dichloro series and the weak ring-
unsubstituted compounds. Thus 8a , 15a , and 18a have
selectivities of SERT/DAT ranging from 20 to 1170 while
the unsubstituted 8d , 15d , and 18d have selectivities
that range from 1 to 190. It may be concluded that a
tight fit between the ligand and the relevant transporter
enhances selectivity. As noted in earlier work,27 the
SERT appears to be more discriminating since DAT
inhibition is often similar across the C3-altered com-
pounds in contrast to SERT inhibition which differs
markedly across the series. Similarly, 20 and 26 (3R)
are more selective than 19 and 23 (3â) (Table 3).
Finally, the orientation of the oxygen at the 6 or 7-
position is not absolutely crucial for biological activity
since both R-, â-, and even “planar” 7-ketones manifest
nanomolar binding affinity at the DAT. Indeed, if this
is so, then the hydrogen bonding between an hydroxyl
at this position and the nitrogen may be of limited
consequence. In this regard, the 7R-OH compound 30b
(Scheme 5) is about half as potent (IC50 ) 3.04 nM) as
the 7â-OH analogue 18a at the DAT (IC50 ) 1.19 nM).
The 7-keto analogue 19 (Scheme 2) remains quite potent
at 14.1 nM. In the 6-OH series, the same holds true;
the 6â 17a binds with an affinity of 6.09 nM, and the
6R 30a manifests an IC50 ) 33.2 nM.
Three conclusions emerge: First, 2â-substitution
provides greater potency than 2R-substitution. Second,
replacement of the C2-ester with a C2-ketone retains
potency at the DAT. Third, both 6R- and 7 R-hydroxy-
lated and 7-keto compounds prove potent DAT inhibi-
tors.
Con clu sion
From these data the following may be concluded:
First, the general SAR of the tropanes is maintained in
that the rank order of substitution at the C3 position
remains 3,4-dichlorophenyl > 2-naphthyl > 4-fluorophe-
nyl > phenyl. Second, the general SAR of the bicyclo-
[3.2.1]octane series is maintained in that the 3R-aryl
compounds are more selective than the 3â-aryl com-
pounds.
A number of bridge hydroxylated 8-aza-tropanes have
been prepared and their affinities at the dopamine and
serotonin transporters have been studied. In general,
both 6- and 7-hydroxylated tropanes have similar
potency to their unsubstituted counterparts but mani-
fest greater selectivity for the DAT. SAR in this series
mimics that found in other tropanes in which 3,4-
dichloro substitution generally confers greatest potency
at the DAT and the unsubstituted phenyl ring at C3 is
least potent. 7-Hydroxylated compounds are slightly
more potent at the DAT than their 6-hydoxylated
counterparts. In accord with known SAR, the 3R-aryl
compounds manifest a marked selectivity for DAT
inhibition. As for other tropanes, the DAT has been
found to be enantioselective and the 1S-isomers are
considerably more potent inhibitors than the 1R enan-
Biologica l En a n tioselectivity. The DAT is enantio-
selective.4-6,40,48-50 Accordingly, we explored the biologi-
cal enantioselectivity of the most active parent bridge
hydroxylated compounds, namely, 8a , 15a , and 18a .
Clearly, (Table 2) the 1S enantiomers are significantly
more potent inhibitors than their 1R counterparts.
Thus, (1S)-8a , (1S)-15a , and (1S)-18a all manifest DAT
IC50 values of 0.3-7.4 nM while the 1R enantiomers
(1R)-8a , (1R)-15a , and (1R)-18a manifest DAT IC50’s

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2627
(10% NEt3, 20% EtOAc in hexanes) and 12.8 g of 6â- and 7â-
hydroxy-2-methoxycarbonyl-8-methyl-3-oxo-8-azabicyclo[3.2.1]-
octane as yellow solids (1a and 1b). The total yield of 6â- and
7â-hydroxy-2-methoxycarbonyl-8-methyl-3-oxo-8-azabicyclo-
tiomers. Finally, introduction of a C2-ethyl ketone, as
in 26, resulted in an extremely potent and selective DAT
inhibitor.
1
[3.2.1]octane was 43.4 g (52%). H NMR of 1a (mixture of the
Exp er im en ta l Section
keto-2R- and keto-2â-epimers and the intermediate enol
compounds) δ 4.18-4.02 (m, 1H), 3.89-3.85 (m, 1H), 3.78, 3.76
(2s, 3H), 3.45-3.36 (m, 1H), 3.21 (d, J ) 6 Hz, 1H), 2.75-2.62
(m, 2H), 2.40, 2.38 (2s, 3H), 2.37-2.22 (m, 1H), 2.1-1.92 (m,
2H). 1H NMR of 1b (observed in the intermediate enol form
only) δ 11.83 (s, 1H), 4.06 (dd, J ) 5.8, 2.0 Hz, 1H), 3.78 (s,
3H), 3.66 (s, 1H), 3.37 (t, J ) 4.7 Hz, 1H), 2.66 (dd, J ) 18.9,
4.6 Hz, 1H), 2.39 (s, 3H), 2.02-1.96 (m, 1H), 1.73 (d, J ) 18.6
Hz, 1H).
NMR spectra were recorded in CDCl3, unless otherwise
mentioned, on a J EOL 300 NMR spectrometer operating at
300.53 MHz for 1H and 75.58 MHz for 13C. TMS was used as
internal standard. Melting points are uncorrected and were
measured on a Gallenkamp melting point apparatus. Thin-
layer chromatography (TLC) was carried out on Baker Si250F
plates. Visualization was accomplished with either UV expo-
sure or treatment with phosphomolybdic acid (PMA). Flash
chromatography was carried out on Baker Silica Gel 40 µM.
Elemental analyses were performed by Atlantic Microlab,
Atlanta, GA. HRMS was performed at Harvard University,
MA. Optical rotations were measured on a Perkin-Elmer 241
Polarimeter. All reactions were conducted under an inert (N2)
atmosphere. [3H]WIN 35,428 (2â-carbomethoxy-3â-(4-fluo-
rophenyl)-N-[3H]methyltropane, 79.4-87.0 Ci/mmol) and [3H]-
citalopram (86.8 Ci/mmol) were purchased from DuPont-New
England Nuclear (Boston, MA). (1S)-(-)-Camphanic chloride
(98% ee) was purchased from Aldrich. A Beckman 1801
scintillation counter was used for scintillation spectrometry.
Bovine serum albumin (0.1%) was purchased from Sigma
Chemicals. (R)-(-)-Cocaine hydrochloride for the pharmaco-
logical studies was donated by the National Institute on Drug
Abuse [NIDA]. Room temperature is ca. 22 °C. TMSBr:
trimethylsilyl bromide. Solution A: 2-hydroxy-2-methylpro-
panol/1,2-dichloroethane, 37:63. Yields have not been opti-
mized.
6-H yd r oxy-2-m et h oxyca r b on yl-8-m et h yl-3-oxo-8-a za -
bicyclo[3.2.1]octa n e (1a ) a n d 7-Hyd r oxy-2-m eth oxyca r -
bon yl-8-m eth yl-3-oxo-8-a za bicyclo[3.2.1]octa n e (1b). Ac-
etonedicarboxylic acid (40 g, 0.27 mol) was added slowly to a
solution of acetic acid (60 mL) and acetic anhydride (43 mL)
at 0 °C. The mixture was stirred below 10 °C. The acid
dissolved slowly and a pale yellow precipitate was formed over
3 h. The product was filtered, washed with glacial acetic acid
(30 mL), and followed by benzene (100 mL). The resultant
white powder was dried at high vacuum to afford 30 g of the
desired acetonedicarboxylic acid anhydride (86%): mp 137-
138 °C (lit.38 137.5-138.5 °C). Cold dry methanol (160 mL)
was added to acetonedicarboxylic acid anhydride (50 g, 0.39
mol). The solution was allowed to stand for 1 h and filtered.
The filtrate, acetonedicarboxylic acid monomethylester,38 was
used directly in the following reaction. A mixture of 2,5-
dimethoxydihydrofuran (53.6 g, 0.41 mol) and 3 M aqueous
HCl (1 L) was allowed to stand for 12 h at 22 °C. The brown
solution was cooled to 0 °C and ice (500 g) was added before
being neutralized with aqueous 3 M NaOH (1 L). Methylamine
hydrochloride (41 g, 0.62 mol) in H2O (300 mL) was added to
this solution followed by the preformed methanol solution (160
mL above) of acetonedicarboxylic acid monomethylester and
sodium acetate (50 g) in H2O (200 mL). The mixture (pH 4.5)
was stirred for 2 days at 22 °C. The resultant red solution was
extracted with hexanes (500 mL × 2) to remove nonpolar
byproducts. The aqueous solution was neutralized and satu-
rated by adding solid K2CO3 (960 g). The saturated solution
was extracted with CH2Cl2 (300 mL × 3), and the combined
extracts were dried over anhydrous K2CO3, filtered, and
concentrated to provide the crude product (21.6 g). The
aqueous solution was extracted with solvent A and the
combined extracts were dried over anhydrous K2CO3, filtered,
and concentrated to provide a pale yellow solid that was found
to be a mixture of 6- and 7-hydroxy-2-methoxycarbonyl-8-
methyl-3-oxo-8-azabicyclo[3.2.1]octanes of good purity (30.6 g)
and were used without further purification. The crude product
obtained from the CH2Cl2 extracts was purified by column
chromatography [10% NEt3, 60% EtOAc in hexanes (30-90%),
followed by 10% NEt3, 5% MeOH, and 85% EtOAc] to afford
6.2 g of a mixture of 6â- and 7â-methoxy-2-methoxycarbonyl-
8-methyl-3-oxo-8-azabicyclo[3.2.1]octane26 as an oil: Rf 0.44
6â-Met h oxym et h oxy-2-m et h oxyca r b on yl-8-m et h yl-3-
oxo-8-a za bicyclo[3.2.1]octa n e (2a ) a n d 7â-Meth oxym eth -
oxy-2-m eth oxycar bon yl-8-m eth yl-3-oxo-8-azabicyclo[3.2.1]-
octa n e (2b). To a solution of a mixture of 6â- and 7â-methoxy-
2-methoxycarbonyl-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane (1a
and 1b) (30.6 g, 140 mmol) in anhydrous CH2Cl2 (600 mL) and
dimethoxymethane (170 mL), p-toluenesulfonic acid mono-
hydrate (31 g, 160 mmol) was added in a 2-L flask fitted with
a Soxhlet extractor containing 4 Å molecular sieves. The
reaction mixture was heated to reflux until complete. The
mixture was cooled and treated with saturated aqueous Na2-
CO3 (200 mL) and extracted with CH2Cl2 (300 mL × 4). The
combined organic extracts were dried over K2CO3, filtered, and
concentrated to obtain a mixture of MOM protected alcohols.
The mixture was separated by column chromatography [(5-
10% NEt3, 65% EtOAc in hexanes (30-50%)] to obtain 6â-
hydroxy-2-methoxycarbonyl-8-methyl-3-oxo-8-azabicyclo[3.2.1]-
octane 2a (11.0 g, 30%) and 7â-hydroxy-2-methoxycarbonyl-
8-methyl-3-oxo-8-azabicyclo[3.2.1]octane 2b (10.6 g, 28%) along
with a mixture of the MOM protected alcohols 2a and 2b (2.9
g, 8%).
2a : yellow oil: Rf 0.55 (10% Et3N in EtOAc); 1H NMR
(mixture of the keto-2R- and keto-2â-epimers and the inter-
mediate enol compounds) δ 11.69 (s, enol H), 4.63, 4.62, 4.60
(3s, 2H), 4.10-3.96 (m, 2H), 3.88 (d, J ) 6.6 Hz, 1H), 3.76,
3.75, 3.74 (3s, 3H), 3.36, 3.34 (2s, 3H), 3.11-2.71 (m, 1H), 2.69,
2.62, 2.41 (3s, 3H) 2.34-1.91 (m, 2H). 2b: yellow solid: Rf
0.38 (10% Et3N, 30% EtOAc, and 60% hexanes); 1H NMR
(observed in the intermediate enol form only) δ 11.77 (s, 1H),
4.69 (d, J ) 6.6 Hz, 1H), 4.63 (d, J ) 6.6 Hz, 1H), 4.06 (dd, J
) 1.6, 7.2 Hz, 1H), 3.81 (s, 1H), 3.79 (s, 3H), 3.45 (dd, J ) 4.6,
6.6 Hz, 1H), 3.36 (s, 3H), 2.75-2.66 (m, 1H), 2.43 (s, 3H), 2.18
(dd, J ) 7.4, 14.3 Hz, 1H), 1.99 (dd, J ) 7.4, 14.3 Hz, 1H),
1.79 (d, J ) 18.7 Hz, 1H).
2-Car bom eth oxy-3-tr iflu or om eth ylsu lfon yloxy-7â-m eth -
oxym eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (3b).
To a solution of 2-carbomethoxy-7â-methoxymethoxy-8-methyl-
3-oxo-8-azabicyclo[3.2.1]octane, 2b (4.25 g, 16.5 mmol) in THF
(150 mL), sodium bistrimethylsilylamide (25 mL; 1.0 M
solution in THF) was added dropwise at -70 °C under
nitrogen. After stirring the solution for 30 min, N-phenyltri-
fluoromethanesulfonimide (7.06 g, 19.8 mmol) was added in
one portion at -70 °C. The reaction was allowed to warm to
22 °C and stirred overnight. The volatile solvents were
removed on a rotary evaporator. The residue was dissolved in
CH2Cl2 (200 mL) and washed with H2O (100 mL) and brine
(100 mL). The dried (MgSO4) CH2Cl2 layer was concentrated
to dryness and purified by flash chromatography (2-10% Et3N,
15-30% EtOAc in hexanes) to afford 3.63 g (57%) of 3b as a
pale yellow oil: Rf 0.29 (10% Et3N, 30% EtOAc, 60% hexanes);
1H NMR of 3b δ 4.74 (d, J ) 6.8 Hz, 1H), 4.65 (d, J ) 6.8 Hz,
1H), 4.21 (dd, J ) 1.6, 7.3 Hz, 1H), 4.0 (s, 1H), 3.83 (s, 3H),
3.56-3.50 (m, 1H), 3.37 (s, 3H), 2.80 (dd, J ) 4.1, 18.4 Hz,
1H), 2.44 (s, 3H), 2.21 (dd, J ) 7.4, 14.0 Hz, 1H), 2.02 (dd, J
) 7.4, 14.1 Hz, 1H), 1.89 (d, J ) 18.7 Hz, 1H); HRMS Cal
(M+1): 390.0856; Found 390.0811.
2-Ca r b om et h oxy-3-(t r iflu or om et h yl)su lfon yloxy-6â-
m eth oxym eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e
(3a ). Prepared as described above for 3b (64%): Rf 0.45 (10%

2628 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
Et3N, 30% EtOAc, 60% hexanes); 1H NMR (100 MHz): δ 4.64
(s, 2H), 4.07 (dd, 1H), 3.81 (s, 3H), 3.5-3.30 (m, 2H), 3.36 (s,
3H), 2.85 (dd, 1H), 2.44 (s, 3H), 2.4-1.8 (m, 3H).
hexane); 1H NMR δ 7.15-7.00 (m, 4H), 4.75 (dd, 2H), 4.29 (dd,
1H), 3.89 (s, 1H), 3.53 (s, 3H), 3.45 (m, 1H), 3.39 (s, 3H), 2.73
(dd, 1H), 2.51 (s, 3H), 2.25 (dd, 1H), 2.07 (dd, 1H), 1.85 (d,
1H).
Gen er a l P r oced u r es for Su zu k i Cou p lin g Rea ction s
to Obta in 4 a n d 5. To a solution of 2â-carbomethoxy-3-
[(trifluoromethyl)sulfonyl]oxy-7â- (or 6â-) methoxymethoxy-8-
methyl-8-azabicyclo[3.2.1]oct-2-ene, 3 (1 equiv) in diethoxy-
methane was added LiCl (2 equiv), Na2CO3 (2 M aqueous
solution, 2 equiv), and the aryl boronic acid (1.1 equiv). The
solution was stirred and deoxygenated by bubbling N2 into the
solution for 15 min before the addition, in one portion, of tris-
(dibenzylideneacetone)dipalladium(0) (0.1 equiv) under a strong
stream of N2. After being further deoxygenated for another
0.5 h, the solution was heated to reflux under N2 until no
starting material remained (∼ 3-6 h) (TLC). The mixture was
cooled to 22 °C and filtered through Celite. The Celite was
washed with EtOAc. The combined organic layers were
separated and the aqueous layer was extracted with EtOAc.
The organic layer was combined and dried over K2CO3. The
solvent was removed and the residue was purified by flash
column chromatography (10% Et3N, 30% EtOAc, 60% hexanes)
to afford the coupled compounds.
2-Car bom eth oxy-3-ph en yl-7â-m eth oxym eth oxy-8-m eth -
yl-8-a za bicyclo[3.2.1]oct-2-en e (5d ). The general procedure
described above was followed. The product was obtained as
an oil (29%): Rf 0.56 (10% Et3N, 30% EtOAc, 70% hexane);
1H NMR δ 7.32-7.27 (m, 3H), 7.12-7.07 (m, 2H), 4.73 (dd,
2H), 4.30 (dd, 1H), 3.89 (s, 1H), 3.50 (s, 3H), 2.47 (m, 1H), 3.38
(s, 3H), 2.76 (dd, 1H), 2.52 (s, 3H), 2.25 (dd, 1H), 2.09 (dd, 1H),
1.88 (d, 1H).
Gen er a l P r oced u r e for Sm I2 Red u ction Rea ction s to
Obta in 9-12. Note that the 3R and 3â isomers are obtained
and are separated by column chromatography. To a THF
(anhydrous, 5-10 mL) solution of 2-carbomethoxy-3-aryl-7- (or
6-) methoxymethoxy-8-azabicyclo[3.2.1]oct-2-ene and anhy-
drous methanol (20 equiv) at -78 °C under N2 was added SmI2
(0.1 M solution in THF, 8 equiv) dropwise. The resulting
solution was kept stirring at -78 °C for 4 h and was then
quenched with H2O (10 mL). After warming the solution to
22 °C, sat. NaHCO3 was added and the precipitate was filtered
through a Celite pad. The pad was washed with EtOAc and
the aqueous layer was back extracted with EtOAc three times.
The organic layers were combined, washed with brine, and
dried over K2CO3. The solvent was removed, and the residue
was purified by two consecutive flash columns (First: 10%
Et3N, 30% EtOAc, 60%, hexanes; second: 5% MeOH, 95%
CHCl3) to obtain the 2â, 3â- (9 and 11) and 2â, 3R- (10 and
12) isomers.
2-Ca r b om et h oxy-3-(3,4-d ich lor op h en yl)-6â-m et h oxy-
m eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (4a ). The
general procedure described above was followed. The product
was obtained as an oil (86%): Rf 0.16 (10% Et3N, 20% EtOAc,
1
70% hexanes); H NMR δ 7.39 (d, 1H), 7.21 (d, 1H), 6.95 (dd,
1H), 4.66 (s, 2H), 4.11 (dd, 1H), 3.95 (d, 1H), 3.35 (s, 3H), 3.39-
3.35 (m, 4H), 2.70 (dd, 1H), 2.54-2.43 (m, 4H), 2.19 (ddd, 1H),
2.02 (d, 1H).
2-Ca r bom eth oxy-3-(2-n a p h th yl)-6â-m eth oxym eth oxy-
8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (4b). The general
procedure described above was followed. The product was
obtained as an oil (53%): Rf 0.36 (10% Et3N, 30% EtOAc, 60%
hexane); 1H NMR δ 7.84-7.77 (m, 3H), 7.59 (s, 1H), 7.50-
7.44 (m, 2H), 7.24 (dd,1H), 4.69 (s, 2H), 4.20 (dd, 1H), 4.00 (d,
1H), 3.43 (s, 3H), 3.41-3.38 (m, 4H), 2.82 (dd, 1H), 2.59-2.50
(m, 4H), 2.26-2.17 (m, 2H).
2-Ca r bom eth oxy-3-(4-flu or op h en yl)-6â-m eth oxym eth -
oxy-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (4c). The gen-
eral procedure described above was followed. The product was
obtained as a yellow oil (93%): Rf 0.12 (10% Et3N, 20% EtOAc,
70% hexane); 1H NMR δ 7.11-6.97 (m, 4H), 4.67 (s, 2H), 4.12
(dd, 1H), 3.94 (d, 1H), 3.49 (s, 3H), 3.38-3.33 (m, 4H), 2.71
(dd, 1H), 2.50-2.44 (m, 4H), 2.19 (ddd, 1H), 2.06 (d, 1H).
2-Car bom eth oxy-3-ph en yl-6â-m eth oxym eth oxy-8-m eth -
yl-8-a za bicyclo[3.2.1]oct-2-en e (4d ). The general procedure
described above was followed. The product was obtained as a
light yellow oil (89%): Rf 0.16 (10% Et3N, 20% EtOAc, 70%
hexane); 1H NMR δ 7.36-7.23 (m, 3H), 7.14-7.11 (m, 2H),
4.67 (s, 2H), 4.16 (dd, 1H), 4.03 (d, 1H), 3.47 (s, 3H), 3.43 (m,
1H), 3.38 (s, 1H), 2.87 (dd, 1H), 2.58-2.51 (m, 4H), 2.23 (ddd,
1H), 2.15 (d, 1H).
2-Ca r b om et h oxy-3-(3,4-d ich lor op h en yl)-7â-m et h oxy-
m eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (5a ). The
general procedure described above was followed. The product
was obtained as an oil (80%): Rf 0.33 (10% Et3N, 20% EtOAc,
70% hexane); 1H NMR (100 MHz) δ 7.40 (d, 1H), 7.19 (d, 1H),
6.93 (dd, 1H), 4.71 (m, 2H), 4.24 (dd, 1H), 3.91 (s, 1H), 3.56 (s,
3H), 3.48 (bs, 1H), 3.39 (s, 3H), 2.52 (s, 3H), 2.90-1.5 (m, 4H);
13C NMR δ 168.3, 144.8, 142.0, 133.4, 132.8, 131.3, 129.9,
128.2, 127.4, 96.4, 83.2, 66.3, 57.5, 56.5, 52.7, 41.5, 36.0, 35.7.
2-Ca r bom eth oxy-3-(2-n a p h th yl)-7â-m eth oxym eth oxy-
8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (5b). The general
procedure described above was followed. The product was
obtained as a yellow oil (100%): Rf 0.52 (10% Et3N, 20%
EtOAc, 70% hexane); 1H NMR δ 7.79 (m, 3H), 7.57 (s, 1H),
7.48 (m, 2H), 7.22 (d, 1H), 4.74 (dd, 2H), 4.35 (dd, 1H), 3.95
(s, 1H), 3.52-3.46 (m, 4H), 3.41 (s, 3H), 2.85 (dd, 1H), 2.58 (s,
3H), 2.27 (dd, 1H), 2.15 (dd, 1H), 1.98 (d, 1H).
2â-Ca r bom eth oxy-3â-(3,4-dich lor op h en yl)-6â-m eth oxy-
m eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (9a ) a n d 2â-
Car bom eth oxy-3r-(3,4-dich lor oph en yl)-6â-m eth oxym eth -
oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (10a ). The title
compounds were prepared as in the general procedure given
above. Compound 9a (an oil: 16%) could not be readily purified
and was therefore carried through to the next step as is (see
14a ). Rf 0.67 (Et3N 10%, EtOAc 30%, hexanes 60%). Compound
10a was obtained as an oil (8%): Rf 0.30 (3% MeOH, CHCl3);
Rf 0.69 (Et3N 10%, EtOAc 30%, hexanes 60%). 1H NMR δ 7.32
(d, 1H), 7.25 (d, 1H), 7.01 (d, 1H), 4.64 (dd, 2H), 4.12 (dd, 1H),
3.59-3.55 (m, 5H), 3.39-3.01 (m, 5H), 2.55 (s, 3H), 2.46-2.25
(m, 3H), 2.10 (dd, 1H), 1.29 (ddd, 1H).
2â-Car bom eth oxy-3â-(2-n aph th yl)-6â-m eth oxym eth oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (9b) a n d 2â-Ca r bo-
m eth oxy-3r-(2-n a p h th yl)-6â-m eth oxym eth oxy-8-m eth yl-
8-a za bicyclo[3.2.1]octa n e (10b). The title compounds were
prepared as in the general procedure given above. Compound
9b was obtained as an oil (38%): Rf 0.30 (3% MeOH/CHCl3);
1H NMR δ 7.75 (t, 3H), 7.65 (s, 1H), 7.46-7.33 (m, 3H), 4.67
(s, 2H), 4.32 (dd, 1H), 3.80 (d, 1H), 3.47 (s, 1H), 3.44 (s, 3H),
3.39 (s, 3H), 2.97-2.91 (m, 2H), 2.68 (dt, 1H), 2.52 (s, 3H),
2.37 (ddd, 1H), 2.27 (dd, 1H), 1.92 (dt, 1H). Compound 10b
1
was obtained as an oil (38%: Rf 0.41 (5% MeOH/CHCl3); H
NMR δ 7.70 (t, 3H), 7.62 (s, 1H), 7.48-7.38 (m, 2H), 7.32 (d,
1H), 4.66 (dd, 2H), 4.19 (dd, 1H), 3.65 (s, 1H), 3.59 (s, 1H),
3.54 (s, 3H), 3.39-3.36 (m, 4H), 2.59 (s, 3H), 2.57-2.46 (m,
2H), 2.10 (ddd, 1H), 2.18 (dd, 1H), 1.53 (ddd, 1H).
2â-Car bom eth oxy-3â-(4-flu or oph en yl)-6â-m eth oxym eth -
oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (9c) a n d 2â-Ca r -
b om et h oxy-3r-(4-flu or op h en yl)-6â-m et h oxym et h oxy-8-
m eth yl-8-azabicyclo[3.2.1]octan e (10c). The title compounds
were prepared as in the general procedure given above.
Compound 9c was obtained as an oil (31%): Rf 0.71 (10% Et3N,
30% EtOAc, 60%/hexane); 1H NMR δ 7.20-7.15 (m, 2H), 6.98-
6.92 (m, 2H), 4.65 (s, 2H), 4.26 (dd, J ) 7.4, 3.3 Hz, 1H), 3.76
(d, J ) 6.6 Hz, 1H), 3.50 (s, 3H), 3.42 (s, 1H), 3.38 (s, 3H),
2.82-2.71 (m, 2H), 2.57-2.48 (m, 4H), 2.35 (ddd, J ) 14.3,
7.4, 3.3 Hz, 1H), 2.19 (dd, J ) 14.3, 7.4 Hz, 1H), 1.78 (m, 1H).
Compound 10c was obtained as an oil (23%): Rf 0.71 (10%
Et3N, 30% EtOAc, 60% hexane); 1H NMR δ 7.15-7.11 (m, 2H),
6.98-6.91 (m, 2H), 4.64 (dd, 2H), 4.13 (dd, J ) 7.1, 3.3 Hz,
1H), 3.60-3.53 (m, 4H), 3.40-3.31 (m, 5H), 2.57 (s, 3H), 2.54-
2-Ca r bom eth oxy-3-(4-flu or op h en yl)-7â-m eth oxym eth -
oxy-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (5c). The gen-
eral procedure described above was followed. The product was
obtained as an oil (100%): Rf 0.53 (10% Et3N, 20% EtOAc, 70%

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2629
2.26 (m, 3H), 2.12 (dd, J ) 14.0, 7.1 Hz, 1H), 1.33 (ddd, J )
4.24 (dd, 1H), 3.60 (s, 3H), 3.51-3.37 (m, 6H), 2.62-2.58 (m,
4H), 2.40 (dt, 1H), 2.20 (ddd, 1H), 2.03 (dd, 1H), 1.25 (dt, 1H).
Gen er a l P r oced u r es for Clea va ge of MOM P r otectin g
Gr ou p . To a solution of MOM protected alcohol in anhydrous
CH2Cl2 containing 4 Å molecular sieves, at 0 °C, was added
TMSBr (10 equiv). The solution was slowly allowed to warm
to 22 °C and stirred overnight. The reaction was quenched by
slow addition of aq NaHCO3 and the aqueous layer was
exhaustively extracted with CH2Cl2. The extracts were com-
bined and dried over K2CO3. The solvent was removed and
residue was purified by flash column chromatography (10%
Et3N, 30-90% EtOAc, 60-0% hexanes) to give the product.
2-Ca r bom eth oxy-3-(3,4-d ich lor op h en yl)-6â-h yd r oxy-8-
m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (7a ). The procedure
described above was followed. A white crystalline solid was
obtained (71%): mp 94.0-96.0 °C; Rf 0.13 (10% Et3N/EtOAc);
1H NMR δ 7.39 (d, 1H), 7.21 (d, 1H), 6.95 (dd, 1H), 4.19 (m,
1H), 3.94 (d, J ) 6.6 Hz, 1H), 3.53 (s, 3H), 3.23 (d, J ) 5.8 Hz,
1H), 2.65 (dd, J ) 19.5, 5.8 Hz, 1H), 2.54-2.48 (m, 4H), 2.25
(bs, 1H), 2.09-1.97 (m, 2H). Anal. (C16H17Cl2NO3) C, H, N.
2-Ca r bom eth oxy-3-(2-n a p h th yl)-6â-h yd r oxy-8-m eth yl-
8-a za bicyclo[3.2.1]oct-2-en e (7b). The procedure described
above was followed to obtain a white powder (29%); mp 165.0-
167.0 °C; Rf 0.15 (10% Et3N/EtOAc); 1H NMR δ 7.84-7.78 (m,
3H), 7.59 (s, 1H), 7.49-7.46 (m, 2H), 7.25-7.22 (m, 1H), 4.26
(dd, J ) 7.4, 3.0 Hz, 1H), 4.00 (d, J ) 6.3 Hz, 1H), 3.45 (s,
3H), 3.27 (d, J ) 5.5 Hz, 1H), 2.77 (dd, J ) 19.5, 5.8 Hz, 1H),
2.62-2.55 (m, 4H), 2.19 (d, J ) 19.5 Hz, 1H), 2.08 (ddd, J )
13.5, 6.6, 2.7 Hz, 1H). Anal. (C20H21NO3) C, H, N.
2-Car bom eth oxy-3-(4-flu or oph en yl)-6â-h ydr oxy-8-m eth -
yl-8-a za b icyclo[3.2.1]oct -2-en e (7c). The procedure de-
scribed above was followed to obtain a white crystalline solid
(22%); mp 124.0-126.0 °C; Rf 0.31 (10% Et3N/EtOAc); 1H NMR
δ 7.39-6.98 (m, 4H), 4.19 (dd, J ) 7.1, 2.7 Hz, 1H), 3.94 (d, J
) 6.6 Hz, 1H), 3.50 (s, 3H), 3.23 (d, J ) 5.5 Hz, 1H), 2.66 (dd,
J ) 19.5, 5 Hz, 1H), 2.55-2.49 (m, 4H), 2.08-2.01 (m, 2H).
Anal. (C16H18FNO3) C, H, N.
2-Ca r bom eth oxy-3-p h en yl-6â-h yd r oxy-8-m eth yl-8-a za -
bicyclo[3.2.1]oct-2-en e (7d ). The procedure described above
was followed to obtain a white crystalline solid (13%); mp
165.0-167.0 °C; Rf 0.22 (10% Et3N/EtOAc); 1H NMR δ 7.39-
7.28 (m, 3H), 7.13-7.10 (m, 2H), 4.21 (dd, J ) 7.4, 3.0 Hz,
1H), 3.94 (d, J ) 6.6 Hz, 1H), 3.48 (s, 3H), 3.23 (d, J ) 5.5 Hz,
1H), 2.70 (dd, J ) 19.5, 5.5 Hz, 1H), 2.57-2.50 (m, 4H), 2.09
(d, J ) 19.8 Hz, 1H), 2.07-2.01 (m, 1H). Anal. (C16H19NO3) C,
H, N.
2-Ca r bom eth oxy-3-(3,4-d ich lor op h en yl)-7â-h yd r oxy-8-
m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (8a ). The procedure
described above was followed. The product was obtained as a
white solid (34%): mp 130.4-132.4 °C; Rf 0.1 (EtOAc); 1H
NMR δ 7.37 (d, 1H), 7.19 (d, 1H), 6.95 (dd, 1H), 4.29 (m, 1H),
3.65 (s, 1H), 3.56 (s, 3H), 3.40 (m, 1H), 2.62 (dd, 1H), 2.48 (s,
3H), 2.08 (m, 2H), 1.80 (d, 1H). Anal. (C16H17Cl2NO3) C, H, N.
(1S )-2-Ca r b om e t h oxy-3-(3,4-d ich lor op h e n yl)-7â-h y-
dr oxy-8-m eth yl-8-azabicyclo[3.2.1]oct-2-en e ((1S)-8a). This
compound was obtained from (1S)-28 (vide infra) via the
procedure described above: [R]2D1 ) -58° (c ) 1.0, CHCl3),
[R]2D1 ) -49° (c ) 0.40, MeOH) (>98% ee from 1H NMR of
(1S)-28) mp 130.4-131.8 °C.
(1R)-2-Ca r b om et h oxy-3-(3,4-d ich lor op h en yl)-7â-h y-
dr oxy-8-m eth yl-8-azabicyclo[3.2.1]oct-2-en e ((1R)-8a). This
compound was obtained from (1R)-2 (vide infra) via the
procedure described above: [R]2D1 +57° (c ) 1.0, CHCl3)
(>98% ee from 1H NMR of (1R)-27) mp 129-131 °C.
2-Ca r bom eth oxy-3-(2-n a p h th yl)-7â-h yd r oxy-8-m eth yl-
8-a za bicyclo[3.2.1]oct-2-en e (8b). The procedure described
above was followed. The product was obtained as a white solid
(57%): mp 164.2-165.2 °C; Rf 0.4 (5% Et3N/EtOAc); 1H NMR
δ 7.80 (m, 3H), 7.58 (s, 1H), 7.48 (m, 2H), 7.26 (m, 1H), 4.35
(m, 1H), 3.79 (s, 1H), 3.44 (m, 4H), 2.74 (dd, 1H), 2.54 (s, 3H),
2.14 (m, 2H), 2.01 (d, 1H). Anal. (C20H21NO3) C, H, N.
2-Car bom eth oxy-3-(4-flu or oph en yl)-7â-h ydr oxy-8-m eth -
yl-8-a za b icyclo[3.2.1]oct -2-en e (8c). The procedure de-
scribed above was followed. The product was obtained as a
14.0, 10.9, 1.6 Hz, 1H).
2â-Ca r b om et h oxy-3â-p h en yl-6â-m et h oxym et h oxy-8-
m et h yl-8-a za b icyclo[3.2.1]oct a n e (9d ) a n d 2â-Ca r b o-
m eth oxy-3r-p h en yl-6â-m eth oxym eth oxy-8-m eth yl-8-a za -
bicyclo[3.2.1]octan e (10d). The title compounds were prepared
as in the general procedure given above. Compound 9d
obtained as an oil (28%): Rf 0.25 (5% MeOH/CHCl3); 1H NMR
δ 7.29-7.13 (m, 5H), 4.66 (s, 2H), 4.27 (dd, J ) 7.1, 3.3 Hz,
1H), 2.77 (m, 1H), 3.48 (s, 3H), 3.43 (s, 1H), 3.38 (s, 3H), 2.86
(t, J ) 4.1 Hz, 1H), 2.79 (dt, J ) 12.9, 4.9 Hz, 1H), 2.60-2.50
(m, 4H), 2.35 (ddd, J ) 14, 6.8, 3.3 Hz, 1H), 2.20 (dd, J ) 14.3,
7.4 Hz, 1H), 1.81 (dt, J ) 12.4, 3.9 Hz, 1H). Compound 10d
obtained as an oil (25%): Rf 0.50 (5% MeOH/CHCl3); 1H NMR
δ 7.29-7.14 (m, 5H), 4.64 (dd, 2H), 4.14 (dd, J ) 7.1, 3.0 Hz,
1H), 3.59-3.57 (m, 4H), 3.48-3.32 (m, 5H), 2.57 (s, 3H), 2.50-
2.37 (m, 2H), 2.29 (ddd, J ) 14.6, 7.1, 3.0 Hz, 1H), 2.1 (dd, J
) 14.3, 7.4 Hz, 1H), 1.4 (ddd, 1H).
2â-Ca r bom eth oxy-3â-(3,4-d ich lor op h en yl)-7â-m eth oxy-
m eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (11a ) a n d
2â-Ca r b om et h oxy-3r-(3,4-d ich lor op h en yl)-7â-m et h oxy-
m eth oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (12a ). The
title compounds were prepared as in the general procedure
given above. Compound 11a obtained as a yellow oil (37%):
Rf 0.52 (5% MeOH/CHCl3); 1H NMR δ 7.35 (d, 1H), 7.30 (d,
1H), 7.10 (dd, 1H), 4.70 (dd, 2H), 4.35 (dd, 1H), 3.62 (s, 1H),
3.54 (m, 4H), 3.42 (s, 3H), 3.00 (m, 1H), 2.72-2.62 (m, 1H),
2.51-2.41 (m, 4H), 2.25 (ddd, 1H), 2.07 (dd, 1H), 1.59 (dt, 1H).
Compound 12a was obtained as a white solid (36%): Rf 0.67
(5% MeOH/CHCl3); 1H NMR δ 7.32 (d, 1H), 7.25 (d, 1H), 7.02
(dd, 1H), 4.66 (dd, 2H), 4.25 (dd, 1H), 3.62 (s, 3H), 3.48-3.32
(m, 6H), 2.54-2.47 (m, 4H), 2.43-2.33 (m, 1H), 2.20 (ddd, 1H),
2.00 (dd, 1H), 1.21 (dt, 1H).
2â-Car bom eth oxy-3â-(2-n aph th yl)-7â-m eth oxym eth oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (11b) a n d 2â-Ca r bo-
m eth oxy-3r-(2-n a p h th yl)-7â-m eth oxym eth oxy-8-m eth yl-
8-a za bicyclo[3.2.1]octa n e (12b). The title compounds were
prepared as in the general procedure given above. Compound
11b was obtained as an oil (29%): Rf 0.41 (5% MeOH/CHCl3);
1H NMR δ 7.80-7.75 (m, 3H), 7.68 (s, 1H), 7.48-7.35 (m, 3H),
4.74 (dd, 2H), 4.44 (dd, 1H), 3.67-3.59 (m, 2H), 3.44 (s, 6H),
3.17 (t, 1H), 2.89 (dt, 1H), 2.69 (dt, 1H), 2.52 (s, 3H), 2.27 (ddd,
1H), 2.15 (dd, 1H), 1.72 (dt, 1H). Compound 12b was obtained
as an oil (26%): Rf 0.31 (5% MeOH/CHCl3); 1H NMR δ 7.78-
7.72 (m, 3H), 7.67 (s, 1H), 6.95-6.88 (m, 3H), 4.67 (dd, 2H),
4.28 (dd, 1H), 3.58 (s, 3H), 3.53 (s, 1H), 3.45-3.37 (m, 5H),
2.50 (t, 1H), 2.47 (s, 3H), 2.42 (dt, 1H), 2.15 (ddd, 1H), 2.00
(dd, 1H), 1.23 (dt, 1H).
2â-Car bom eth oxy-3â-(4-flu or oph en yl)-7â-m eth oxym eth -
oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (11c) a n d 2â-Ca r -
b om et h oxy-3r-(4-flu or op h en yl)-7â-m et h oxym et h oxy-8-
m eth yl-8-azabicyclo[3.2.1]octan e (12c). The title compounds
were prepared as in the general procedure given above.
Compound 11c was obtained as an oil (35%): Rf 0.63 (EtOAc);
1H NMR δ 7.22-7.18 (m, 2H), 6.98-6.91 (m, 2H), 4.71 (dd,
2H), 4.38 (dd, 1H), 3.62-3.57 (m, 2H), 3.50 (s, 3H), 3.42 (s,
3H), 2.99 (t, 1H), 2.87-2.78 (m, 1H), 2.57-2.48 (m, 4H), 2.22
(ddd, 1H), 2.06 (dd, 1H), 1.61 (dt, 1H). Compound 12c was
obtained as a solid (40%): Rf 0.36 (10% Et3N, 30% EtOAc, 60%
1
hexanes); H NMR δ 7.16-7.10 (m, 2H), 6.97-6.91 (m, 2H),
4.66 (dd, 2H), 4.24 (dd, 1H), 3.59 (s, 3H), 3.46 (m, 1H), 3.39-
3.33 (m, 5H), 2.51 (t, 1H), 2.48 (s, 3H), 2.38 (dt, 1H), 2.19 (ddd,
1H), 2.01 (dd, 1H), 1.24 (dt, 1H).
2â-Ca r b om et h oxy-3â-p h en yl-7â-m et h oxym et h oxy-8-
m eth yl-8-a za bicyclo[3.2.1]octa n e (11d ) a n d 2â-Ca r bo-
m eth oxy-3r-p h en yl-7â-m eth oxym eth oxy-8-m eth yl-8-a za -
bicyclo[3.2.1]octan e (12d). The title compounds were prepared
as in the general procedure given above. Compound 11d was
1
obtained as an oil (25%): Rf 0.15 (EtOAc); H NMR δ 7.29-
7.22 (m, 4H), 7.18-7.12 (m, 1H), 4.71 (dd, 2H), 4.37 (dd, 1H),
3.61-3.57 (m, 2H), 3.48 (s, 3H), 3.43 (s, 3H), 3.03 (t, 1H), 2.80-
2.69 (dt, 1H), 2.60-2.48 (m, 4H), 2.25 (ddd, 1H), 2.07 (dd, 1H),
1.62 (dt, 1H). Compound 12d was obtained as an oil (31%):
Rf 0.50 (EtOAc); 1H NMR δ 7.30-7.12 (m, 5H), 4.65 (dd, 2H),

2630 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
yellow gum (58%): Rf 0.23 (10% Et3N/EtOAc); 1H NMR δ 7.15-
6.96 (m, 4H), 4.30 (m, 1H), 3.75 (s, 1H), 3.50 (s, 3H), 3.41 (m,
1H), 2.85 (bs, 1H), 2.64 (dd, 1H), 2.48 (s, 3H), 2.08 (m, 2H),
1.85 (d, 1H). Anal. (C16H18FNO3) C, H, N.
2-Ca r bom eth oxy-3-p h en yl-7â-h yd r oxy-8-m eth yl-8-a za -
bicyclo[3.2.1]oct-2-en e (8d ). The procedure described above
was followed to provide a white solid (62%): mp 113-114 °C;
Rf 0.23 (10% Et3N/EtOAc); 1H NMR δ 7.36-7.30 (m, 3H), 7.15-
7.08 (m, 2H), 4.31 (m, 1H), 3.73 (s, 1H), 3.51 (s, 3H), 3.41 (m,
1H), 2.66 (dd, 1H), 2.50 (s, 3H), 2.09 (m, 2H), 1.88 (d, 1H).
Anal. (C16H19NO3) C, H, N.
2â-Ca r bom eth oxy-3â-(3,4-d ich lor op h en yl)-6â-h yd r oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (14a ). The procedure
described above was followed to provide a white solid (88%):
mp 93.5-95.5 °C; Rf 0.18 (5% MeOH/CH2Cl2); 1H NMR δ 7.33
(d, 1H), 7.28 (d, 1H), 7.06 (dd, 1H), 4.44 (m, 1H), 3.84 (m, 1H),
3.51 (s, 3H), 3.30 (m, 1H), 2.79 (m, 1H), 2.68 (m, 1H), 2.56 (s,
3H), 2.45 (dt, 1H), 2.32-2.18 (m, 2H), 1.76 (m, 1H). Anal.
(C16H19Cl2NO3) C, H, N.
2â-Ca r bom eth oxy-3â-(2-n a p h th yl)-6â-h yd r oxy-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e (14b). The procedure described
above was followed to provide a white solid (89%): mp 84.0-
86.0 °C; Rf 0.23 (10% MeOH/CH2Cl2); 1H NMR δ 7.76 (t, 3H),
7.65 (s, 1H), 7.48-7.35 (m, 3H), 4.53 (m, 1H), 3.87 (m, 1H),
3.44 (s, 3H), 3.37 (m, 1H), 2.97-2.90 (m, 2H), 2.68 (dd, 1H),
2.60 (s, 3H), 2.32 (m, 2H), 1.93 (m, 1H), 1.78 (m, 1H). Anal.
(C20H23NO3) C, H, N.
2â-Ca r b om et h oxy-3â-(4-flu or op h en yl)-6â-h yd r oxy-8-
m eth yl-8-a za bicyclo[3.2.1]octa n e (14c). The procedure de-
scribed above was followed to provide a white solid (30%): mp
162.0-164.0 °C; Rf 0.21 (10% MeOH/CH2Cl2); 1H NMR δ 7.71
(m, 2H), 6.95 (m, 2H), 4.48 (m, 1H), 3.83 (m, 1H), 3.50 (s, 3H),
3.31 (s, 1H), 2.82-2.71 (m, 2H), 2.57 (s, 3H), 2.52 (dt, 1H),
2.35-2.21 (m, 2H), 1.79-1.75 (m, 2H). Anal. (C16H20FNO3) C,
H, N.
2â-Ca r b om et h oxy-3â-p h en yl-6â-h yd r oxy-8-m et h yl-8-
a za bicyclo[3.2.1]octa n e (14d ). The procedure described
above was followed to provide a white solid (33%): mp 150.0-
152.0 °C; Rf 0.13 (10% MeOH/CH2Cl2); 1H NMR δ 7.2-7.14
(m, 5H), 4.50 (m, 1H), 3.85 (m, 1H), 3.48 (s, 3H), 3.36 (m, 1H),
2.88-2.75 (m, 2H), 2.60 (s, 3H), 2.55 (dd, 1H), 2.29 (m, 2H),
1.81 (m, 1H). Anal. (C16H21NO3) C, H, N.
2â-Ca r bom eth oxy-3â-(3,4-d ich lor op h en yl)-7â-h yd r oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (15a ). The procedure
described above was followed to provide a colorless crystalline
solid (68%): mp 185.5-186.5 °C; Rf 0.47 (10% Et3N/EtOAc);
1H NMR δ 7.32 (d, 1H), 7.29 (d, 1H), 7.07 (dd, 1H), 4.53 (m,
1H), 3.60 (m, 1H), 3.53 (s, 3H), 3.00 (t, J ) 3.8 Hz, 1H), 2.68-
2.64 (m, 1H), 2.55 (s, 3H), 2.50-2.44 (m, 1H), 2.23-2.08 (m,
2H), 1.78 (d, J ) 3.8 Hz, 1H), 1.59 (m, 1H). Anal. (C16H19Cl2-
NO3) C, H, N.
2â-Ca r b om et h oxy-3â-p h en yl-7â-h yd r oxy-8-m et h yl-8-
a za bicyclo[3.2.1]octa n e (15d ). The procedure described
above was followed to obtain a white crystalline solid (17%):
mp 165.8-167.8 °C; Rf 0.13 (5% MeOH/CHCl3); 1H NMR δ
7.30-7.13 (m, 5H), 4.58 (dd, J ) 6.6, 4.1 Hz, 1H), 3.62 (m,
1H), 3.53 (s, 1H), 3.49 (s, 3H), 3.06 (m, 1H), 2.75 (m, 1H), 2.57
(m, 4H), 2.22-2.11 (m, 2H), 1.64-1.59 (m, 1H). Anal. (C16H21
NO3) C, H, N.
-
2â-Ca r bom eth oxy-3r-(3,4-d ich lor op h en yl)-6â-h yd r oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (17a ). The procedure
described above was followed to obtain a white powder (18%):
mp 129.1-131.1 °C; Rf 0.57 (10% Et3N/EtOAc); 1H NMR δ 7.34
(d, 1H), 7.26 (d, 1H), 7.02 (dd, 1H), 4.25 (m, 1H), 3.64-3.61
(m, 4H), 3.48-3.35 (m, 1H), 3.20 (d, 1H), 2.65 (s, 3H), 2.38-
2.08 (m, 4H), 1.90 (bs, 1H), 1.29 (dd, 1H). Anal. (C16H19Cl2-
NO3) C, H, N.
2â-Ca r bom eth oxy-3r-(2-n a p h th yl)-6â-h yd r oxy-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e (17b). The procedure described
above was followed to provide a white solid (77%): mp 93.5-
94.5 °C; Rf 0.45 (0.5% MeOH/CH2Cl2); 1H NMR δ 7.77 (m, 3H),
7.63 (s, 1H), 7.45 (m, 2H), 7.32 (d, 2H), 4.29 (m, 1H), 3.68 (m,
2H), 3.57 (s, 3H), 3.23 (d, 1H), 2.70 (s, 3H), 2.63 (d, 1H), 2.41
(dt, 1H), 2.21 (m, 2H), 1.54 (dd, 1H). Anal. (C20H23NO3) C, H,
N.
2â-Ca r b om et h oxy-3r-(4-flu or op h en yl)-6â-h yd r oxy-8-
m eth yl-8-a za bicyclo[3.2.1]octa n e (17c). The procedure de-
scribed above was followed to provide a yellow crystalline solid
1
(39%): mp 148.0-150.0 °C; Rf 0.53 (10% MeOH/CH2Cl2); H
NMR δ 7.13 (dd, 2H), 6.97 (t, 2H), 4.26 (m, 1H), 3.64-3.59
(m, 4H), 3.43 (m 1H), 3.21 (d, 1H), 2.67 (s, 3H), 2.40-2.12 (m,
4H), 1.31 (dd, 1H). Anal. (C16H20FNO3) C, H, N.
2â-Ca r b om et h oxy-3r-p h en yl-6â-h yd r oxy-8-m et h yl-8-
a za bicyclo[3.2.1]octa n e (17d ). The procedure described
above was followed to provide a white powder (22%): mp
138.0-140.0 °C; Rf 0.21 (10% Et3N/EtOAc); 1H NMR δ 7.30-
7.12 (m, 5H), 4.24 (m, 1H), 3.66-3.60 (m, 4H), 3.48 (dd, J )
17.9, 9.1 Hz, 1H), 3.21 (d, J ) 8.8 Hz, 1H), 2.68 (s, 3H), 2.49
(d, J ) 9.1 Hz, 1H), 2.42-2.32 (m, 1H), 2.25-2.17 (m, 2H),
1.45-1.36 (m, 1H). Anal. (C16H21NO3) C, H, N.
2â-Ca r bom eth oxy-3r-(3,4-d ich lor op h en yl)-7â-h yd r oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (18a ). The procedure
described above was followed to provide a colorless solid
(87%): mp 148.5-150 °C; Rf 0.18 (10% Et3N, 40% EtOAc, 50%
1
hexane); Rf 0.53 (10% Et3N/EtOAc); H NMR δ 7.31 (d, 1H),
7.26 (d, 1H), 7.25 (dd, 1H), 4.29 (m, 1H), 3.61 (s, 3H), 3.47-
3.38 (m, 2H), 3.27 (s, 1H), 2.67 (s, 3H), 2.42-2.32 (m, 2H),
2.17-2.01 (m, 3H), 1.26 (dd, 1H). Anal. (C16H19Cl2NO3) C, H,
N.
(1S)-2â-Ca r bom eth oxy-3r-(3,4-d ich lor op h en yl)-7â-h y-
d r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e ((1S)-18a ). Ob-
tained from (1S)-8a : [R]2D1 ) -48° (c ) 1.0, CHCl3); [R]21
)
-36° (c ) 0.40, MeOH) (>98% ee from 1H NMR of (1S)D-27)
mp 148.5-150 °C.
(1S)-2â-Ca r bom eth oxy-3â-(3,4-d ich lor op h en yl)-7â-h y-
d r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e ((1S)-15a ). Ob-
tained from (1S)-8a (vide infra) [R]2D1 ) +25° (c ) 1.3, CHCl3)
(>98% ee from 1H NMR of (1S)-28) mp 185.5-186.5 °C.
(1R)-2â-Ca r bom eth oxy-3â-(3,4-d ich lor op h en yl)-7â-h y-
d r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e ((1R)-15a ). Ob-
tained from (1R)-2 (vide infra) [R]2D1 ) -26° (c ) 1.3, CHCl3)
(>98% ee from 1H NMR of (1R)-27) mp 186-187 °C.
2â-Ca r bom eth oxy-3â-(2-n a p h th yl)-7â-h yd r oxy-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e (15b). The procedure described
above was followed to provide a white crystalline solid: (78%);
(1R)-2â-Ca r bom eth oxy-3r-(3,4-d ich lor op h en yl)-7â-h y-
d r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e ((1R)-18a ). Ob-
tained from (1R)-2: [R]2D1 ) +47° (c ) 1.0, CHCl3) (>98% ee
from 1H NMR of (1R)-27) mp 149-150 °C.
2â-Ca r bom eth oxy-3r-(2-n a p h th yl)-7â-h yd r oxy-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e (18b). The procedure described
above was followed to provide a yellow crystalline solid
(62%): mp 140.1-141.9 °C; Rf 0.20 (5% MeOH/CH2Cl2); 1H
NMR δ 7.82-7.76 (m, 3H), 7.63 (s, 1H), 7.49-7.41 (m, 2H),
7.32 (d, 1H), 4.33 (m, 1H), 3.64 (m, 1H), 3.57 (s, 3H), 3.50 (m,
1H), 3.32 (s, 1H), 2.73 (s, 3H), 2.67 (d, 1H), 2.20-2.08 (m, 3H),
1.53-1.46 (m, 1H). Anal. (C20H23NO3) C, H, N.
2â-Ca r b om et h oxy-3r-(4-flu or op h en yl)-7â-h yd r oxy-8-
m eth yl-8-a za bicyclo[3.2.1]octa n e (18c). The procedure de-
scribed above was followed to obtain a white crystalline solid
(47%): mp 177.2-179.0 °C; Rf 0.12 (EtOAc); 1H NMR δ 7.18-
7.10 (m, 2H), 6.99-6.93 (m, 2H), 4.29 (m, 1H), 3.59 (s, 3H),
3.51-3.38 (m, 2H), 3.26 (s, 1H), 2.70 (s, 3H), 2.47-2.35 (m,
2H), 2.18-2.00 (m, 2H), 1.29 (m, 1H). Anal. (C16H20FNO3) C,
H, N.
1
mp 207.5-208.5 °C; Rf 0.15 (10% MeOH/CHCl3); H NMR δ
7.76 (t, 3H), 7.65 (s, 1H), 7.47-7.35 (m, 3H), 4.63 (t, 1H), 3.66
(m, 1H), 3.58 (s, 1H), 3.45 (s, 3H), 3.17 (m, 1H), 2.97-2.87 (m,
1H), 2.67 (dt, 1H), 2.60 (s, 3H), 2.28-2.19 (m, 2H), 1.85 (bs,
1H), 1.76-1.70 (m, 1H). Anal. (C20H23NO3) C, H, N.
2â-Ca r b om et h oxy-3â-(4-flu or op h en yl)-7â-h yd r oxy-8-
m eth yl-8-a za bicyclo[3.2.1]octa n e (15c). The procedure de-
scribed above was followed to obtain a white crystalline solid
(11%): mp 179.3-181.3 °C; Rf 0.53 (10% Et3N/EtOAc); 1H
NMR δ 7.18 (m, 2H), 6.96 (m, 2H), 4.59 (m, 1H), 3.67-3.61
(m, 2H), 3.50 (s, 3H), 3.03 (m, 1H), 2.79-2.50 (m, 5H), 2.20
(m, 2H), 1.61 (m, 1H). Anal. (C16H20FNO3) C, H, N.

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2631
2â-Ca r b om et h oxy-3r-p h en yl-7â-h yd r oxy-8-m et h yl-8-
a za bicyclo[3.2.1]octa n e (18d ). The procedure described
above was followed to provide a white powder (26%): mp
165.0-167.0 °C; Rf 0.19 (5% MeOH/CH2Cl2); 1H NMR δ 7.31-
7.15 (m, 5H), 4.29 (m, 1H), 3.59 (s, 3H), 3.52-3.42 (m, 2H),
3.29 (s, 1H), 2.71 (s, 3H), 2.54-2.36 (m, 2H), 2.18-2.02 (m,
2H), 1.39 (dd, 1H). Anal. (C16H21NO3) C, H, N.
(m, 5H), 3.27 (m, 1H), 2.84 (dd, J ) 7.9, 1.9 Hz, 1H), 2.59-
2.30 (m, 2H), 2.44 (s, 3H), 1.92 (d, J ) 18.4 Hz, 1H), 1.52 (ddd,
J ) 14.0, 8.5, 1.9 Hz, 1H). Anal. (C16H17Cl2NO3) C, H, N.
(b) 2â-Ca r bom eth oxy-3â-(3,4-d ich lor op h en yl)-8-m eth -
yl-8-a za bicyclo[3.2.1]oct-7-on e (19). 2â-Carbomethoxy-3â-
(3,4-dichlorophenyl)-7â-hydroxy-8-methyl-8-azabicyclo[3.2.1]-
octane, 15 was treated as described above and the product was
obtained as a white solid (170 mg, 81%): mp 84.4-86.4 °C; Rf
P r ep a r a tion of 7r- a n d 6r-Hyd r oxy Tr op a n es (30). (a )
2â-Car bom eth oxy-3r-(3,4-dich lor oph en yl)-7r-ben zoyloxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (29b). To a solution of
2â-carbomethoxy-3R-(3,4-dichlorophenyl)-7â-hydroxy-8-meth-
yl-8-azabicyclo[3.2.1]octane, 18a (0.46 g, 1.34 mmol) in THF
(20 mL) with benzoic acid (0.49 g, 4.0 mmol) and triph-
enylphosphine (0.70 g, 2.68 mol) was added diethyl azodicar-
boxylate (DEAD) (0.46 g, 2.68 mmol) dropwise at 0 °C. The
reaction was kept stirring overnight at 22 °C. The solvent was
removed and the residue was purified by a flash column
chromatography (30% hexanes in EtOAc) to give the product
as a white solid (0.43 g, 72%). Rf 0.53 (30% hexane, 70%
1
0.60 (10% Et3N, 30% EtOAc, 60% hexanes); H NMR δ 7.35
(d, 1H), 7.32 (d, 1H), 7.09 (dd, 1H), 3.75 (dt, J ) 5.2, 1.3 Hz,
1H), 3.56 (s, 3H), 3.34 (s, 1H), 3.22 (t, J ) 3.8 Hz, 1H), 2.98
(dt, J ) 4.7, 12.9 Hz, 1H), 2.84 (dt, J ) 12.7, 3.3 Hz, 1H), 2.73
(dd, J ) 18.7, 7.4 Hz, 1H), 2.39 (s, 3H), 2.12 (d, J ) 18.7 Hz,
1H), 1.86 (dt, J ) 12.1, 3.3 Hz, 1H). Anal. (C16H17Cl2NO3) C,
H, N.
P r ep a r a tion of 2â-Eth yl Keton e Tr op a n es (23 a n d
26). (a ) 2â-Ca r bo-N-m eth oxy-N-m eth yla m in o-3r-(3,4-d i-
ch lor oph en yl)-7â-m eth oxym eth oxy-8-m eth yl-8-azabicyclo-
[3.2.1]octa n e (24) (Weinreb amide). To a solution of N,O-
dimethylhydroxylamine hydrochloride (0.34 g, 3.48 mmol) in
CH2Cl2 (10 mL) was added Al(CH3)3 dropwise at -12 °C
(glycol-dry ice bath) under N2. The resulting solution was
stirred for 10 min at -12 °C before the cooling bath was
removed and the reaction stirred at 22 °C for 30 min. The
reaction was cooled to -12 °C and a solution of 2â-car-
bomethoxy-3R-(3,4-dichlorophenyl)-7â-methoxymethoxy-8-meth-
yl-8-azabicyclo[3.2.1]octane, 12a (0.45 g, 1.16 mmol) in CH2Cl2
(4 mL) was transferred by cannula into the reaction flask and
the reaction was stirred for 1 h at -12 °C and then 2 h at 22
°C. Rochelle’s salt solution (potassium sodium tartrate satu-
rated in water) (∼ 1 mL) was added and the mixture was
stirred vigorously. Water was added to dissolve some solid salt
and the aqueous layer was extracted with CHCl3 (6 × 20 mL).
The organic layers were combined and dried over K2CO3. The
solvent was removed. The residue was purified by passing it
through a short silica gel column (10% Et3N in EtOAc) to afford
a white solid (0.47 g, 89%). Rf 0.39 (10% Et3N, 30% EtOAc,
1
EtOAc); H NMR δ 8.06 (dd, 2H), 7.65 (d, 1H), 7.49 (t, 2H),
7.32 (d, 1H), 7.28 (d, 1H), 7.07 (dd, 1H), 5.68 (m, 1H), 3.73 (d,
1H), 3.55 (s, 3H), 3.48-3.31 (m, 2H), 3.10 (d, 1H), 3.01-2.85
(m, 1H), 2.53-2.47 (m, 4H), 1.64 (dd, 1H), 1.41 (dt, 1H).
(b) 2â-Ca r bom eth oxy-3r-(3,4-d ich lor op h en yl)-6r-ben z-
oyloxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (29a ). 2â-Car-
bomethoxy-3R-(3,4-dichlorophenyl)-6â-hydroxy-8-methyl-8-aza-
bicyclo[3.2.1]octane, 17a (0.23 g) was treated as described
above for the 7-hydroxy compound. A white solid was obtained
1
(0.19 g, 63%): Rf 0.77 (30% hexane, 70% EtOAc); H NMR δ
8.14-8.02 (m, 2H), 7.63-7.46 (m, 3H), 7.29 (dd, 2H), 7.05 (dd,
1H), 5.60 (m, 1H), 3.68-3.60 (m, 4H), 3.45-3.35 (m, 2H), 3.11-
2.93 (m, 1H), 2.63-2.49 (m, 4H), 2.30-2.15 (m, 1H), 1.85-
1.95 (m, 2H).
(c) 2â-Ca r b om et h oxy-3r-(3,4-d ich lor op h en yl)-7r-h y-
d r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (30b). To a solu-
tion of 2â-carbomethoxy-3R-(3,4-dichlorophenyl)-7R-benzoyloxy-
8-methyl-8-azabicyclo[3.2.1]octane 29b (0.43 g, 0.95 mmol) in
THF (26 mL) was added LiOH (0.085 g, 1.9 mmol in 5 mL
H2O). The resulting solution was stirred for 5 h at 22 °C and
quenched with aqueous HCl (3%). The THF was removed and
the aqueous layer was extracted with CHCl3 (6 × 20 mL). The
organic layers were combined and dried over K2CO3. The
solvent was removed and the residue was purified by column
chromatography (10% Et3N in EtOAc) to afford the product
as a white gum which solidified slowly upon standing (0.19 g,
26%): mp 121-123 °C; Rf 0.41 (10% Et3N/EtOAc); 1H NMR δ
7.36 (d, 1H), 7.33 (d, 1H), 7.12 (dd, 1H), 4.79 (ddd, J ) 9.9,
6.0, 3.8 Hz, 1H), 3.59 (s, 3H), 3.46-3.33 (m, 3H), 3.24 (t, J )
7.9 Hz, 1H), 2.83-2.68 Hz (m, 1H), 2.55-2.43 (m, 4H), 1.40-
1.25 (m, 2H). Anal. (C16H19Cl2NO3) C, H, N.
1
60% hexane); H NMR δ 7.29 (d, 1H), 7.26 (d, 1H), 7.05 (dd,
1H), 4.67 (dd, J ) 3.6, 6.8 Hz, 2H), 4.37 (dd, J ) 7.1, 3.3 Hz,
1H), 3.56 (s, 3H), 3.54-3.46 (m, 2H), 3.14 (m, 1H), 3.10 (s, 3H),
2.65 (d, J ) 11.3 Hz, 1H), 2.54 (s, 3H), 2.48-2.37 (m, 1H),
2.26-2.18 (m, 1H), 2.02 (dd, J ) 14.0, 7.4 Hz, 1H), 1.16-1.07
(m, 1H).
(c)2â-Carbo-N-methoxy-N-methylamine-3â-(3,4-dichloro-
ph en yl)-7â-m eth oxym eth oxy-8-m eth yl-8-azabicyclo[3.2.1]-
octa n e (21) (Weinreb amide). The starting material 11a (0.47
g, 1.2 mmol) was treated as for the 3R compound shown above.
A solid was obtained (0.31 g, 61%): Rf 0.45 (10% Et3N, 30%
EtOAc, 60% hexane); 1H NMR δ 7.31 (d, 1H), 7.31 (d, 1H),
7.11 (dd, 1H), 4.69 (s, 2H), 4.34 (dd, J ) 7.7, 3.6 Hz, 1H), 3.66
(s, 3H), 3.61-3.58 (m, 2H), 3.42 (s, 3H), 3.28 (m, 1H), 3.05 (s,
3H), 2.74-2.68 (m, 2H), 2.49 (s, 3H), 2.28-2.20 (m, 1H), 2.09-
2.02 (m, 1H), 1.60-1.56 (m, 1H).
(d ) 2â-Ca r bom eth oxy-3r-(3,4-d ich lor op h en yl)-6r-h y-
d r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (30a ). 2â-Car-
bomethoxy-3R-(3,4-dichlorophenyl)-6R-benzoyloxy-8-methyl-8-
azabicyclo[3.2.1]octane 29a (0.18 g, 0.39 mmol) was treated
as described above and a white solid was obtained (51 mg,
(d ) 1-[3r-(3,4-Dich lor op h en yl)-7â-m eth oxym eth oxy-8-
m eth yl-8-a za bicyclo[3.2.1]oct-2-yl]p r op a n -1-on e (25). To
a solution of 2â-carbo-N-methoxy-N-methylamino-3R-(3,4-
1
38%): mp 161.2-162.2 °C; Rf 0.26 (10% Et3N in EtOAc); H
NMR δ 7.35 (d, 1H), 7.34 (d, 1H), 7.11 (dd, 1H), 4.72 (m, 1H),
3.57 (s, 3H), 3.37-3.25 (m, 3H), 2.88-2.77 (m, 1H), 2.50 (d,
1H), 2.42 (s, 3H), 2.20-1.97 (m, 2H), 1.52 (dd, 1H). Anal.
(C16H19Cl2NO3) C, H, N.
dichlorophenyl)-7â-methoxymethoxy-8-methyl-8-azabicyclo-
[3.2.1]octane, 24 (0.47 g, 1.13 mmol) in THF (anhydrous, 15
mL) was added ethylmagnesium bromide (3.4 mL, 1 M in THF)
dropwise at 0 °C under N2. The reaction was slowly warmed
to 22 °C and stirred overnight. The reaction was then quenched
with aqueous sat. NH4Cl solution. The THF was replaced by
CH2Cl2. The aqueous layer was extracted by CHCl3 (6 × 20
mL). The organic solution was dried over K2CO3 and solvent
was removed to afford a white solid (0.45 g, ∼100%). The
sample was used for the next reaction without further puri-
fication. Rf 0.67 (10% Et3N, 30% EtOAc, 60% hexane); 1H NMR
δ 7.30 (d, 1H), 7.23 (d, 1H), 7.00 (dd, 1H), 4.68 (dd, J ) 8.5,
1.7 Hz, 2H), 4.24 (dd, J ) 7.4, 3.6 Hz, 1H), 3.47-3.31 (m, 5H),
3.20 (s, 1H), 2.56-2.31 (m, 6H), 2.27-1.99 (m, 3H), 1.22-1.13
(m, 1H), 0.96 (t, J ) 7.1 Hz, 3H).
Oxid a tion of 7-Hyd r oxy Tr op a n es to 7-Keton es (19 a n d
20). (a ) 2-â-Ca r b om et h oxy-3r-(3,4-d ich lor op h en yl)-8-
m eth yl-8-a za bicyclo[3.2.1]oct-7-on e (20). A solution of 2â-
carbomethoxy-3R-(3,4-dichlorophenyl)-7â-hydroxy-8-methyl-8-
azabicyclo[3.2.1]octane 18 (0.20 g, 0.58 mmol) in CH2Cl2 (5 mL)
containing N-methylmorpholine N-oxide (1.5 equiv) and 4 Å
molecular sieves (0.5 g; powder) was stirred for 10 min at 22
°C under N2 and then treated with tetra-n-propylammonium
perruthenate (10% molar equiv). The resulting solution was
stirred overnight. The solvent was removed and the residue
was purified by flash column chromatography (10% Et3N, 30%
EtOAc, 60% hexanes) to afford a white solid (0.16 g, 80%): mp
163.5-164.5 °C; Rf 0.47 (10% Et3N, 30% EtOAc, 60% hexanes);
1H NMR δ 7.34 (d, 1H), 7.29 (d, 1H), 7.02 (dd, 1H), 3.68-3.60
(e) 1-[3â-(3,4-Dich lor op h en yl)-7â-m eth oxym eth oxy-8-
m eth yl-8-azabicyclo[3.2.1]oct-2-yl]pr opan -1-on e (22). Wein-
reb amide 21 (0.31 g, 0.74 mmol) was treated as described

2632 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
above to obtain a white solid product (0.27 g, 95%). Rf 0.71
(10% Et3N, 30% EtOAc, 60% hexane); 1H NMR δ 7.30 (d, 1H),
7.27 (d, 1H), 7.06 (dd, 1H), 4.72 (s, 2H), 4.31 (dd, J ) 7.4, 3.6
Hz, 1H), 3.59-3.54 (m, 2H), 3.44 (s, 3H), 3.12 (m, 1H), 2.68-
2.66 (m, 1H), 2.52-2.40 (m, 5H), 2.30-2.17 (m, 2H), 2.05 (dd,
J ) 14.3, 7.7 Hz, 1H), 1.62-1.55 (m, 1H), 0.92 (t, J ) 7.1 Hz,
3H).
1H), 4.24 (t, J ) 4.4 Hz, 1H), 3.71 (s, 3H), 3.64 (m, 1H), 3.35
(m, 1H), 2.97 (s, 1H), 2.78 (s, 1H), 2.61 (s, 3H), 2.53 (dd, J )
13.1, 7.4 Hz, 1H), 2.15 (m, 1H), 2.02 (m, 1H), 1.69 (d, J ) 14.3
Hz, 1H). Anal. (C23H25F2NO4) C, H, N.
(d ) 2â-Ca r bom eth oxy-3r-bis(4-flu or op h en yl)m eth oxy-
6â-h yd r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (32a ). 2â-
Carbomethoxy-3R-hydroxy-6â-methoxymethoxy-8-methyl-8-
azabicyclo[3.2.1]octane 31a (0.54 g, 2.10 mmol) was treated
as described above and the product was obtained as a white
(f) 1-[3r-(3,4-Dich lor op h en yl)-7â-h yd r oxy-8-m eth yl-8-
a za bicyclo[3.2.1]oct-2-yl]p r op a n -1-on e (26). The deprotec-
tion of the MOM group of 25 was carried out by the general
method described earlier. 2â-(1-Propanoyl)-3R-(3,4-dichlorophe-
nyl)-7â-methoxymethoxy-8-methyl-8-azabicyclo[3.2.1]octane
(0.27 g) was used and the product was obtained as a white
solid (0.23 g, 76%): mp 113.1-114.1 °C; Rf 0.25 (10% Et3N,
1
foam. (0.17 g, 17%): Rf 0.32 (10% MeOH/CHCl3); H NMR δ
7.25 (dd, J ) 8.5, 5.8 Hz, 4H), 6.99 (dt, J ) 8.5, 0.8 Hz, 4H),
5.34 (s, 1H), 4.48 (dd, J ) 7.2, 2.8 Hz, 1H), 4.20 (m, 1H), 3.73
(s, 3H), 3.61 (d, J ) 8.0 Hz, 1H), 3.26 (s, 1H), 3.17 (s, 1h), 2.88
(bs, 1H), 2.58 (s, 3H), 2.48 (dd, J ) 13.7, 7.14 Hz, 1H), 2.07
(ddd, J ) 14.0, 7.4, 2.7 Hz, 1H), 1.97 (d, J ) 16.8 Hz, 1H).
Anal. (C23H25F2NO4) C, H, N.
1
30% EtOAc, 60% hexanes); H NMR δ 7.32 (d, 1H), 7.22 (d,
1H), 6.97 (dd, 1H), 4.27 (m, 1H), 3.50-3.41 (m, 2H), 3.06 (s,
1H), 2.67 (s, 3H), 2.67 (s, 3H), 2.52-2.32 (m, 3H), 2.18-2.01
Resolu tion of 7-Hyd r oxy Tr op a n on e. (a ) (1R)-2-Ca r -
b om et h oxy-3-(1′S)-ca m p h a n yl-7â-m et h oxym et h oxy-8-
m eth yl-8-a za bicyclo[3.2.1]oct-2-en e (27). To a solution of
racemic 2â-carbomethoxy-7â-methoxymethoxy-8-methyl-3-oxo-
8-azabicyclo[3.2.1]octane 2b (7.1 g, 27.6 mmol) in THF (an-
hydrous, 100 mL) cooled at -78 °C, NaN(TMS)2 (35.9 mL, 1
M in THF) was added dropwise by syringe. The resulting
solution was stirred for 45 min. At -78 °C and (1S)-(-)-
camphanic chloride (8.3 g, 38.6 mmol) was added. The solution
was stirred overnight, during which time it slowly warmed to
22 °C. The reaction was quenched with sat. NaHCO3 (20 mL).
The THF was replaced with CH2Cl2. The organic layer was
separated and aqueous layer was back extracted with CH2Cl2
(6 × 20 mL). The organic extracts were combined and dried
over K2CO3 and solvent was removed. The residue was purified
by flash chromatography (5% MeOH in EtOAc) to afford the
product (7.75 g, 64%) as a yellow oil which solidified upon
standing for 3 days. NMR showed two diastereoisomers in the
sample. The (1R,1′S) diastereoisomer was separated by re-
crystallization (5 times) from benzene/heptane to give dias-
teromerically pure 27 as a white solid (1.4 g, 36%, > 98% de
by 1H NMR). Despite repeated efforts, the (1S,1′S) diastere-
(m, 3H), 1.25 (m, 1H), 0.94 (t, J ) 7.4 Hz, 3H). Anal. (C17H21
Cl2NO2) C, H, N, Cl.
-
(g) 1-[3â-(3,4-Dich lor op h en yl)-7â-h yd r oxy-8-m eth yl-8-
a za bicyclo[3.2.1]oct-2-yl]p r op a n -1-on e (23). The deprotec-
tion of the MOM group of 22 was carried out by the general
method described earlier. 2â-(1-Propanoyl)-3â-(3,4-dichlorophe-
nyl)-7â-methoxymethoxy-8-methyl-8-azabicyclo[3.2.1]octane
(0.28 g) was used and the product was obtained as a white
solid (0.18 g, 73%): mp 195.5-196.5 °C;. Rf 0.39 (10% Et3N,
1
30% hexanes, 60% EtOAc); H NMR δ 7.31 (d, 1H), 7.26 (d,
1H), 7.05 (dd, 1H), 4.59 (p, J ) 3.3 Hz, 1H), 3.60 (m, 1H), 3.52
(m, 1H), 3.10 (dd, J ) 4.4, 3.3 Hz, 1H), 2.65-2.41 (m, 6H),
2.26 (q, J ) 7.4 Hz, 2H), 2.24-2.09 (m, 2H), 1.86 (d, J ) 3.8
Hz, 1H), 0.92 (t, J ) 7.4 Hz, 3H). Anal. (C17H21Cl2NO2) C, H,
N.
P r ep a r a tion of 7 a n d 6-Hyd r oxy Diflu or op in es (32).
(a ) 2â-Ca r bom eth oxy-3r-h yd r oxy-7â-m eth oxym eth oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (31b). To a solution of
2â-carbomethoxy-7â-methoxymethoxy-8-methyl-3-oxo-8-aza-
bicyclo[3.2.1]octane 1b (1.0 g, 3.89 mmol) in MeOH (100 mL)
was added NaBH4 (0.36 g, 9.72 mmol) at -78 °C. The mixture
was kept in a freezer (-25 °C) for 3 days. The reaction was
quenched with H2O (40 mL) and MeOH was removed. The
aqueous layer was extracted with CH2Cl2 (6 × 20 mL). The
extracts were combined and dried over K2CO3 and solvent was
removed. The residue was purified by gradient flash chroma-
tography (5% MeOH in CHCl3 to 10% MeOH in CHCl3) to give
the product as a yellow oil (0.53 g, 52%). Rf 0.21 (10% MeOH/
CHCl3); 1H NMR δ 4.67-4.58 (m, 3H), 4.29 (t, 1H), 3.77 (s,
3H), 3.52 (m, 1H), 3.34 (s, 3H), 3.31-3.23 (m, 2H), 2.93 (t, 1H),
2.58 (dd, 1H), 2.54 (s, 3H), 2.06-1.98 (m, 2H), 1.66 (d, 1H).
(b) 2â-Car bom eth oxy-3r-h ydr oxy-6â-m eth oxym eth oxy-
8-m eth yl-8-a za bicyclo[3.2.1]octa n e (31a ). 2â-Carbometh-
oxy-6â-methoxymethoxy-8-methyl-3-oxo-8-azabicyclo[3.2.1]-
octane 1a (1.0 g) was treated as described above to obtain the
product as an oil (0.53 g, 52%). Rf 0.21 (10% MeOH/CHCl3);
1H NMR δ 4.64 (s, 2H), 4.59 (dd, 1H), 4.28 (m, 1H), 3.74 (s,
3H), 3.59 (m, 1H), 3.46 (s, 1H), 3.36 (s, 3H), 3.17 (s, 1H), 2.89
(m, 1H), 2.63-2.55 (m, 4H), 2.09-1.95 (m, 2H), 1.76 (d, 1H).
1
omer could not be isolated pure. The H NMR of the diaster-
eomeric mixture is provided below. Of particular interest is
the region 1.2-0.7 ppm as in benzene-d6 the two diastereomers
show different chemical shifts. 1H NMR (C6D6) δ 4.70 (m, 1H),
4.55 (m, 1H), 4.19 (m, 1H), 4.11 (m, 1H), 3.28 (m, 3H), 3.21
(m, 3H), 2.9 (m, 1H), 2.35 (m, 3H), 2.34-2.18 (m, 2H), 2.11-
2.02 (m, 2H), 1.66 (m, 1H), 1.29-1.21 (m, 4H), 1.026 (s, 3H,
1S,1′S), 0.992 (s, 3H, 1R,1′S), 0.897 (s, 3H, 1S,1′S), 0.890 (s,
3H, 1R,1′S), 0.817 (s, 3H, 1S,1′S), 0.803 (s, 3H, 1R,1′S).
The (1R,1′S) product of recrystallization 27 was diastereo-
merically pure (>98% de) as confirmed by the complete
absence of the (1S,1′S)-diastereomer at 1.015 ppm. Rf 0.42 (5%
MeOH/EtOAc); 1H NMR (C6D6) δ 4.70 (d, J ) 6.6 Hz, 1H), 4.55
(d, J ) 6.6 Hz, 1H), 4.19 (dd, J ) 7.4, 2.2 Hz, 1H), 4.11 (s,
1H), 3.28 (s, 3H), 3.21 (s, 3H), 2.9 (m, 1H), 2.35 (s, 3H), 2.34-
2.18 (m, 2H), 2.11-2.02 (m, 2H), 1.66 (dd, J ) 13.4, 7.4 Hz,
1H), 1.29-1.21 (m, 4H), 0.98 (s, 3H), 0.89 (s, 3H), 0.78 (s, 3H).
(b ) (1R)-7â-Met h oxym et h oxy-2-m et h oxyca r b on yl-8-
m eth yl-3-oxo-8-a za bicyclo[3.2.1]octa n e ((1R)-2). A solu-
tion of (1R)-2-carbomethoxy-3-(1′S)-camphanyl-7â-hydroxy-8-
methyl-8-azabicyclo[3.2.1]oct-2-ene 27 (1.40 g, 3.20 mmol) in
THF (50 mL) was treated with LiOH aqueous solution (0.26
g, 6.4 mmol, 16 mL H2O) and the resulting solution was stirred
at 22 °C for 3 h. The THF was removed in vacuo and K2CO3
(8 g) was added to the aqueous solution which was exhaus-
tively extracted with CH2Cl2. The CH2Cl2 extracts were
combined and dried over K2CO3. Solvent was removed to
obtain a white solid (1R-2) (0.89 g) that was used for the
ensuing steps without further purification. 1H NMR δ 4.67 (d,
1H), 4.54 (d, 1), 3.98 (s, 1H), 3.93 (dd, 1H), 3.30 (s, 3H), 3.21
(s, 3H), 2.92 (dd, 1H), 2.43 (m, 1H), 2.50 (dd, 1H), 2.21 (s, 3H),
2.05 (dd, 1H), 1.51 (dd, 1H), 1.42 (d, 1H).
(c) 2â-Ca r bom eth oxy-3r-bis(flu or op h en yl)m eth oxy-7â-
h yd r oxy-8-m eth yl-8-a za bicyclo[3.2.1]octa n e (32b). A solu-
tion of 2â-carbomethoxy-3R-hydroxy-7â-methoxymethoxy-8-
methyl-8-azabicyclo[3.2.1]octane 31b (0.52 g, 2.04 mmol) and
4,4′-difluorobenzhydrol (0.53 g, 2.22 mmol) in CH2Cl2 (50 mL)
with p-toluenesulfonic acid (0.39 g, 2.04 mmol) was placed in
a round-bottom flask equipped with a Soxhlet condenser in
which a thimble filled with molecular sieves (3 Å) was placed.
The reaction was heated to reflux overnight during which time
the molecular sieves were replaced with fresh sieves several
times. The reaction was quenched with sat. NaHCO3 and the
aqueous layer was extracted with CH2Cl2. The extracts were
combined and dried over K2CO3 and solvent was removed on
a rotary evaporator. The residue was purified by column
chromatography (5% MeOH in EtOAc to 10% MeOH in EtOAc)
to afford the desired product as a white solid (0.21 g, 22%):
(c) (1S)-2-Ca r b om et h oxy-3-(3,4-d ich lor op h en yl)-7â-
(1′S)-ca m p h a n yloxy-8-m et h yl-8-a za b icyclo[3.2.1]oct -2-
en e (28). A solution of racemic 2-carbomethoxy-3-(3,4-
dichlorophenyl)-7â-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-2-
1
mp 150-152 °C; Rf 0.09 (5% MeOH, EtOAc); H NMR δ 7.25
(dd, 4H), 6.99 (m, 4H), 5.45 (s, 1H), 4.42 (dd, J ) 7.1, 2.8 Hz,

Synthesis of 6- and 7-Hydroxy-8-azabicyclo[3.2.1]octanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2633
ene 8a (11.1 g, 32 mmol) in CH2Cl2 (250 mL) with Et3N (6.8
mL, 48.7 mmol) was treated with 1S-(-)-camphanic chloride
(10.5 g, 48.7 mmol) at 0 °C. The resulting solution was stirred
overnight at 22 °C and then quenched with NaHCO3 (sat.).
The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The organic layers were
combined and dried over MgSO4. The solvent was removed and
the crude product containing the two diastereoisomers was
separated by two consecutive gravity columns (10% Et3N, 30%
EtOAc, 60% hexanes). The pure (1S,1′S) product 28 (2.4 g) was
obtained as a yellow solid. A further 1.8 g was obtained as a
mixture of diastereomers: Rf (one elution: both diastereomers
run together) 0.14 (10% Et3N, 30% EtOAc, 60% hexane); Rf
(two elutions) (1S,1′S) 0.25 (1R,1′S) 0.18 (10% Et3N, 30%
EtOAc, 60% hexane).
The 1H NMR of 28 showed no trace of the (1R,1S) diaste-
reomer and was therefore diastereomerically pure (de > 98%).
1H NMR (C6Dd) δ 7.08 (d, 1H), 7.02 (d, 1H), 6.47 (dd, J ) 8.3,
2.2 Hz, 1H), 5.34 (dd, J ) 7.4, 2.2 Hz, 1H), 4.16 (s, 1H), 3.15
(s, 3H), 2.89 (dd, J ) 6.9, 4.7 Hz, 1H), 2.19 (s, 3H), 2.17-2.07
(m, 2H), 1.98 (dd, J ) 18.4, 5.2 Hz, 1H), 1.82-1.65 (m, 2H),
1.25-1.09 (m, 3H), 0.92 (s, 3H), 0.82 (s, 3H), 0.72 (s, 3H).
Primate Research Center. We recently cloned the DAT and
SERT from both species and found them to have virtually
identical protein sequences.51 The caudate-putamen was dis-
sected from coronal slices and yielded 1.4 ( 0.4 g of tissue.
Membranes were prepared as described previously. Briefly,
the caudate-putamen was homogenized in 10 volumes (w/v)
of ice-cold Tris‚HCl buffer (50 mM, pH 7.4 at 4 °C) and
centrifuged at 38000g for 20 min in the cold. The resulting
pellet was suspended in 40 volumes of buffer, and the entire
procedure was repeated twice. The membrane suspension (25
mg of original wet weight of tissue/mL) was diluted to 12 mL/
mL for [3H]WIN 35,428 or [3H]citalopram assay in buffer just
before the assay and was dispersed with a Brinkmann Polytron
homogenizer (setting #5) for 15 s. All experiments were
conducted in triplicate, and each experiment was repeated in
each of 2-3 preparations from individual brains.
Dop a m in e Tr a n sp or ter Assa y. The dopamine transporter
was labeled with [3H]WIN 35,428 ([3H]CFT, (1R)-2â-car-
bomethoxy-3â-(4-fluorophenyl)-N-[3H]methyltropane, 81-84
Ci/mmol, DuPont-NEN). The affinity of [3H]WIN 35,428 for
the dopamine transporter was determined in experiments by
incubating tissue with a fixed concentration of [3H]WIN 35,-
428 and a range of concentrations of unlabeled WIN 35,428.
The assay tubes received, in Tris‚HCl buffer (50 mM, pH 7.4
at 0-4 °C; NaCl 100 mM), the following constituents at a final
assay concentration: WIN35,428, 0.2 mL (1 pM - 100 or 300
nM), [3H]WIN 35,428 (0.3 nM); membrane preparation 0.2 mL
(4 mg of original wet weight of tissue/mL). The 2 h incubation
(0-4 °C) was initiated by addition of membranes and termi-
nated by rapid filtration over Whatman GF/B glass fiber filters
presoaked in 0.1% bovine serum albumin (Sigma Chem. Co.).
The filters were washed twice with 5 mL of Tris‚HCl buffer
(50 mM) and incubated overnight at 0-4 °C in scintillation
fluor (Beckman Ready-Value, 5 mL), and radioactivity was
measured by liquid scintillation spectrometry (Beckman 1801).
Cpm were converted to dpm following determination of count-
ing efficiency (> 45%) of each vial by external standardization.
Total binding was defined as [3H]WIN 35,428 bound in the
presence of ineffective concentrations of unlabeled WIN 35,-
428 (1 or 10 pM). Nonspecific binding was defined as [3H]WIN
35,428 bound in the presence of an excess (30 µM) of (-)-
cocaine. Specific binding was the difference between the two
values. Competition experiments to determine the affinities
of other drugs at [3H]WIN 35,428 binding sites were conducted
using procedures similar to those outlined above. Stock solu-
tions of water-soluble drugs were dissolved in water or buffer
and stock solutions of other drugs were made in a range of
ethanol/HCl solutions or other appropriate solvents. Several
of the drugs were sonicated to promote solubility. The stock
solutions were diluted serially in the assay buffer and added
(0.2 mL) to the assay medium as described above. IC50 values
were computed by the EBDA computer program and are the
means of experiments conducted in triplicate.
Ser oton in Tr a n sp or ter Assa y. The serotonin transporter
was assayed in caudate-putamen membranes using conditions
similar to those for the dopamine transporter. The affinity of
[3H]citalopram (spec. act.: 82 Ci/mmol, DuPont-NEN) for the
serotonin transporter was determined in experiments by
incubating tissue with a fixed concentration of [3H]citalopram
and a range of concentrations of unlabeled citalopram. The
assay tubes received, in Tris‚HCl buffer (50 mM, pH 7.4 at
0-4 °C; NaCl 100 mM), the following constituents at a final
assay concentration: citalopram, 0.2 mL (1 pM - 100 or 300
nM), [3H]citalopram (1 nM); membrane preparation 0.2 mL
(4 mg original wet weight of tissue/mL). The 2-h incubation
(0-4 °C) was initiated by addition of membranes and termi-
nated by rapid filtration over Whatman GF/B glass fiber filters
presoaked in 0.1% polyethyleneimine. The filters were washed
twice with 5 mL of Tris‚HCl buffer (50 mM) and incubated
overnight at 0-4 °C in scintillation fluor (Beckman Ready-
Value, 5 mL), and radioactivity was measured by liquid
scintillation spectrometry (Beckman 1801). Cpm were con-
verted to dpm following determination of counting efficiency
(> 45%) of each vial by external standardization. Total binding
(d ) (1R)-2-Ca r b om et h oxy-3-(3,4-d ich lor op h en yl)-7â-
ca m p h a n oyl-8-m eth yl-8-a za bicyclo[3.2.1]oct-2-en e ((1R)-
28). To confirm that the above compound is 1S configured, a
similar reaction was carried out by using the 1R ene com-
1
pound. H NMR (C6D6) δ 7.11 (d, 1H), 7.05 (d, 1H), 6.52 (dd,
1H), 5.36 (dd, J ) 7.4, 2.2 Hz, 1H), 4.18 (s, 1H), 3.17 (s, 3H),
2.94 (dd, J ) 6.9, 4.7 Hz, 1H), 2.20 (s, 3H), 2.16-1.98 (m, 3H),
1.84 (dd, J ) 14.3, 7.6 Hz, 1H), 1.74-1.65 (m, 1H), 1.25-1.10
(m, 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.75 (s, 3H).
Sin gle-Cr ysta l X-r a y An a lysis of (1R)-8a . Monoclinic
crystals of the purified (1R)-8a were obtained from CH2Cl2/
heptane. A representative crystal was selected and a data set
was collected at room temperature. Pertinent crystal, data
collection and refinement parameters: crystal size, 0.66 × 0.50
× 0.22 mm; cell dimensions, a ) 18.382 (1) Å, b ) 6.860 (1) Å,
c ) 16.131 (1) Å, R ) 90°, â ) 124.65 (1) °, γ ) 90°; formula,
C
16H17Cl2NO3; formula weight ) 342.21; volume ) 1673.3 (2)
Å3; calculated density ) 1.358 g cm-3; space group ) C2;
number of reflections ) 1749 of which 1528 were considered
independent (Rint ) 0.0300). Refinement method was full-
matrix least-squares on F2. The final R-indices were [I > 2σ
(I)] R1 ) 0.0364, wR2 ) 0.0987.
Sin gle-Cr ysta l X-r a y An a lysis of (1R)-18a . Monoclinic
crystals of the purified (1R)-18a were obtained from ethyl CH2-
Cl2/heptane. A representative crystal was selected and a data
set was collected at room temperature. Pertinent crystal, data
collection, and refinement parameters: crystal size, 0.72 × 0.30
× 0.14 mm; cell dimensions, a ) 5.981 (1) Å, b ) 7.349 (1) Å,
c ) 18.135 (1) Å, R ) 90°, â ) 96.205 (6) °, γ ) 90°; formula,
C
16H19Cl2NO3; formula weight ) 344.22; volume ) 792.29 (12)
Å3; calculated density ) 1.443 g cm-3; space group ) P21;
number of reflections ) 1630 of which 1425 were considered
independent (Rint ) 0.0217). Refinement method was full-
matrix least-squares on F2. The final R-indices were [I > 2σ
(I)] R1 ) 0.0298, wR2 ) 0.0858.
Sin gle-Cr ysta l X-r a y An a lysis of (1S)-18a . Monoclinic
crystals of the purified (1S)-18a were obtained from CH2Cl2/
heptane. A representative crystal was selected and a data set
was collected at room temperature. Pertinent crystal, data
collection, and refinement parameters: crystal size, 0.64 × 0.32
× 0.18 mm; cell dimensions, a ) 15.000 (1) Å, b ) 7.018 (1) Å,
c ) 15.886 (1) Å, R ) 90°, â ) 99.34 (1) °, γ ) 90°; formula,
C
16H19Cl2NO3; formula weight ) 344.22; volume ) 1650.1 (2)
Å3; calculated density ) 1.386 g cm-3; space group ) P2(1);
number of reflections ) 3267 of which 2979 were considered
independent (Rint ) 0.0285). Refinement method was full-
matrix least-squares on F2. The final R-indices were [I > 2σ
(I)] R1 ) 0.0449, wR2 ) 0.1236.
Tissu e Sou r ces a n d P r ep a r a tion . Brain tissue from adult
male and female cynomolgus monkeys (Macaca fasicularis)
and rhesus monkeys (Macaca mulatta) was stored at -85 °C
in the primate brain bank at the New England Regional

2634 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Meltzer et al.
was defined as [3H]citalopram bound in the presence of
ineffective concentrations of unlabeled citalopram (1 or 10 pM).
Nonspecific binding was defined as [3H]citalopram bound in
the presence of an excess (10 µM) of fluoxetine. Specific binding
was the difference between the two values. Competition
experiments to determine the affinities of other drugs at [3H]-
citalopram binding sites were conducted using procedures
similar to those outlined above. IC50 values were computed
by the EBDA computer program and are the means of
experiments conducted in triplicate.
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nonane derivatives. J . Med. Chem. 1996, 39, 4744-4749.
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Stoelwinder, J . Synthesis of the 6- and 7-hydroxylated cocaines
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7- methoxy tropanes. Tetrahedron Lett. 1997, 38, 1121-1124.
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relationships of inhibition of the dopamine transporter by
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(28) Zhao, L.; Kozikowski, A. P. Corrigendum to Synthesis of the 2â,
3â-, 2R, 3â-, 2â, 3R- and 2R, 3R- isomers of 6â-hydroxy-3-(p-tolyl)-
tropane-2-carboxylic acid methyl ester. Tetrahedron Lett. 1999,
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Ack n ow led gm en t. This work was supported by the
National Institute on Drug Abuse (P.M.: DA7-8081;
DA11542; B.K.M.: DA 06303, DA 11558, DA00304,
RR00168) and by the Office of Naval Research (CHG).
We thank Radhika Narang, Keiko Akasofu, Helen
Panas, and J odie Basner for excellent technical as-
sistance.
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra,
ORTEP drawings of (1R)-8a , (1R)-18a , and (1S)-18a , crystal
data and refinement parameters, coordinates, anisotropic
temperature factors, distances and angles. This material is
available free of charge via the Internet at http://pubs.acs.org.
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