Synthesis and biological evaluation of bicyclic and tricyclic substituted nortropane derivatives: Discovery of a novel selective α1D- adrenergic receptor ligand

Article abstract of DOI:10.1016/j.bmc.2004.07.063

A range of 3,6,6-trisubstituted nortropane derivatives based upon 6β-phenyltropane-3β,6 α-diol have been synthesised from 6β-hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were assessed for pharmacological affinity and selectivity at α₁-adrenergic receptors, and 6β-phenyl-8-azabicyclo[3.2.1]octan-3-spiro-2′-(1′, 3′-dioxolane)-6-ol, a novel lead compound selective for the alpha _1D-adrenergic receptor, is reported.

Full text of DOI:10.1016/j.bmc.2004.07.063

Bioorganic & Medicinal Chemistry 12(2004) 5639–5650
Synthesis and biological evaluation of bicyclic and
tricyclic substituted nortropane derivatives: discovery of a
novel selective a1D-adrenergic receptor ligand
b
c
b
Susan J. McGinty,a, Angela Finch, Renate Griffith, Robert M. Graham
*
and John B. Bremnera
aInstitute for Biomolecular Science and Department of Chemistry, University of Wollongong, Northfields Ave, Wollongong,
NSW, 2522, Australia
bVictor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW, 2010, Australia
cSchool of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, 2308, Australia
Received 1 July 2004; revised 28 July 2004; accepted 28 July 2004
Available online 1 September 2004
Abstract—A range of 3,6,6-trisubstituted nortropane derivatives based upon 6b-phenyltropane-3b,6a-diol have been synthesised
from 6b-hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were
assessed for pharmacological affinity and selectivity at a1-adrenergic receptors, and 6b-phenyl-8-azabicyclo[3.2.1]octan-3-spiro-20-
(10,30-dioxolane)-6-ol, a novel lead compound selective for the alpha1D-adrenergic receptor, is reported.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
H
N
H
N
D
D
OH
C
OH
B
As part of an ongoing programme, we have been pursu-
ing the development of structurally novel and pharma-
cologically selective alpha1 (a1)-adrenergic receptor
(AR) ligands,1,2 specifically for the a1B-AR, for thera-
peutic use in cardiovascular disease,3 and the a1D-AR,
for which there are few selective ligands.3c,4a With this
purpose in mind, a design model was constructed incor-
porating a constrained folded conformation of the
adrenaline motif, and containing structural features
based upon the phenethylamine class of adrenergic
receptor ligands. As shown in Figure 1a, this design mo-
tif consisted of an aromatic hydrophobic bonding region
(A), a hydrogen bond acceptor/hydrogen bond donor
region (B), a carbon spacer (C) and a basic amine (to
form a H-bond reinforced salt-bridge when protonated)
(D). The rationale for the incorporation of a folded con-
formation of the adrenaline motif was based upon pre-
liminary qualitative pharmacophore work we have
undertaken, and the possibility that the flexible side
HO
HO
N
A
B
B
D
C
C
A
OH
A
6-substituted tropane
2-substituted tropane
Adrenaline motif
Figure 1a. Presence of the adrenaline motif in bicyclic tropane
derivatives, consisting of an aromatic hydrophobic bonding region
(A), a hydrogen bond acceptors/hydrogen bond donor region (B), a
carbon spacer (C) and a basic amine (to form a H-bond reinforced salt-
bridge when protonated) (D).
chain of adrenaline has a folded bioactive conformation.
Whilst conformationally constrained analogues of
adrenaline and noradrenaline have been studied4b in
the past (for example those in Fig. 1b), we were inter-
ested in greater structural variety.
Our laboratory has an interest in the chemistry and
pharmacology of the tropane family of alkaloids.5–8 In
the development of a1-adrenergic ligands with a con-
strained folded conformation, and containing an ionisa-
ble nitrogen atom, bicyclic derivatives with a tropane
framework provide a novel alternative. An important
Keywords: a1-Adrenergic receptor; 6b-Hydroxytropinone; 3,6,6-Tri-
substituted nortropanes; Microwave assisted reactions.
*
Corresponding author. Tel.: +61 242213501; fax: +61 242214287;
e-mail: susanmc@uow.edu.au
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.063

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S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
novel 3,6,6-trisubstituted nortropane derivatives 1–3
CH3
H
SCH3
N
(Fig. 2), with incorporation of both phenyl and catechol
substituents. The catechol moiety is an important fea-
ture in the adrenergic receptor–ligand interaction, and
derivative 2 would be a particularly interesting com-
pound for a1-adrenergic receptor pharmacological
investigations.
N
H3C
H3C
CH3
NH2
CH3 OH
OCH3
Oxymetazoline
SKF-89748
Figure 1b. SKF-89748 and oxymetazoline: conformationally con-
strained analogues of adrenaline.
2. Results and discussion
2.1. Synthesis of 3,6,6-trisubstituted nortropane
derivatives
structural feature of tropanes is that of rigidity. Whilst
the six-membered ring portion of the molecule may
interconvert between chair and boat forms, the fixed
conformation of the five-membered pyrrolidine ring
provides a rigid framework. This feature renders bicyclic
bridged derivatives such as tropanes useful scaffolds
when a fixed chemical geometry is desired. This was cer-
tainly appealing in the present work with respect to
mimicking a fixed conformation of the adrenaline motif.
The tropane framework therefore provides a similar
geometry to that of a folded conformation of adrenaline
(Fig. 1a), with the additional feature of being held in a
relatively rigid heterocycle.
The 3,6,6-trisubstituted nortropanes 1–3 may be ob-
tained straightforwardly via a route from commercially
available 6b-hydroxytropinone (Scheme 1). The synthe-
sis therefore began with the protection of the hindered
6b-hydroxyl group of 6b-hydroxytropinone as its tert-
butyldimethylsilyl ether 5 in good yield (Scheme 1).
2,2,2-Trichloroethylchloroformate is a favoured reagent
for tropinone N-demethylation, producing the trichloro-
ethyl carbamate from tropinone in a high yield (95%).12
The conditions of carbamate cleavage to furnish the
nortropane (zinc/acetic acid) are moderate (62% yield),
and sufficiently mild to leave the aryl hydroxyl moiety
of the target derivatives intact.12 Treatment of 5 with
2,2,2-trichloroethylchloroformate12 afforded 6, in good
yield. In an attempt to reduce the lengthy reaction time,
carbamate formation was investigated under novel
microwave reaction conditions,13,14 rapidly furnishing
6 in a reasonable yield.
Incorporation of the adrenaline motif into bicyclic tro-
pane-based ligands may be achieved by substitution at
the 6- and 2-positions of the skeleton (Fig. 1a). Exami-
nation of the literature reveals that nortropane based
compounds similar to 1 (Fig. 2) have been investigated
previously for pharmacological activity: 6b-aryltropan-
6-ols based on 4 were explored some twenty years ago
as low potency morphine-like analgesics9 and later as
low potency opiate agonists/antagonists10 such as 4a.
Further 6-phenyl-8-azabicyclo[3.2.1]octanes and octenes
based on 4 have been prepared and they display poten-
tial antidepressant, analgesic and unspecified cardiovas-
cular activity.11 There was no evidence for 2-aryltropan-
2-ol derivatives such as 4b having previously been
developed.
Two different ketal functionalities were then investigated
for protection of the ketone functionality in 6, the cyclic
1,3-dioxolane and the dimethyl ketal. Initially, 6 was
treated with ethanediol and chlorotrimethylsilane15 to
furnish the 1,3-dioxolane derivative 7 in good yield
(Scheme 2). The tert-butyldimethylsilyl protecting group
was removed by treating 7 with tetrabutylammonium
fluoride to yield 8 in moderate yield. In order to reduce
the reaction time when synthesising 7, the ketalisation of
6 was again investigated using microwave conditions
and this afforded, somewhat surprisingly, compound 8
directly and rapidly, rather than 7. This is a potential
alternative method for desilylation of TBDMS ethers,
and for selective ketone protection and alcohol depro-
Whilst 2-arylhydroxytropane derivatives fit the desired
adrenaline motif, their synthetic production would be
via a lengthy route from cocaine derivatives. It was
therefore decided to undertake the synthesis of the 6-
arylhydroxytropane derivatives first and ascertain their
pharmacological activity. Target ligands included the
H
N
H
H
N
N
HO
O
OH
HO
O
OH
OH
HO
H
OH
OH
2
1
3
(CH2)2COPh
Me
N
H
N
N
Aryl
OH
OH
OAc
4
4a
4b
Figure 2. 3,6,6-Trisubstituted tropane target derivatives (1–3); published 2- and 6-arylhyroxynortropane derivatives (4, 4a, 4b).

S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
5641
CO2CH2CCl3
H3C
CO2CH2CCl3
N
H3C
N
N
N
c
a
b
TBDMSO
TBDMSO
TBDMSO
HO
O
O
O
O
O
6β-hydroxytropinone
5
6
7
e
d
CO2CH2CCl3
N
CO2CH2CCl3
N
CO2CH2CCl3
CO2CH2CCl3
N
N
f
g
Ar
Ar
HO
O
O
O
O
O
O
OH
OH
O
O
8
9
10 Ar = Phenyl
11 Ar = 3,4-(OCH2O)-Ph
12 Ar = Phenyl
13 Ar = 3,4-(OCH2O)-Ph
Scheme 1. Reagents and conditions: (a) 2,6-lutidine, tert-butyldimethylsilyltrifluoromethanesulfonate, DCM, OꢂC-rt, N2, 3h, 86% yield; (b) 2,2,2-
trichloroethylchloroformate, K2CO3 (anhydrous), benzene (anhydrous), reflux, N2, 4h, 85% yield; (c) ethanediol, chlorotrimethylsilane, DCM,
reflux, 48h, 86% yield; (d) TBAF, THF, 69% yield; (e) ethanediol, acetonitrile, chlorotrimethylsilane, 80ꢂC, microwave, 25min, 83% yield; (f) H3PO4,
DMSO, rt, 3h, 78% yield; (g) ArMgBr, THF/ether, rt, 3h, 75–77% yield.
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
N
N
N
N
a
b
c
TBDMSO
HO
Ar
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
O
OH
O
20
6
21
22 Ar = Phenyl
23 Ar = 3,4-(OCH2O)-Ph
d
CO2CH2CCl3
N
CO2CH2CCl3
CO2CH2CCl3
N
N
e
Ar
+
Ar
Ar
OH
OH
O
OH
OH
O
H
14 Ar = Phenyl
15 Ar = 3,4-(OCH2O)-Ph
26 Ar = Phenyl
27 Ar = 3,4-(OCH2O)-Ph
18 Ar = Phenyl
19 Ar = 3,4-(OCH2O)-Ph
Scheme 2. Reagents and conditions: (a) trimethylorthoformate, p-TsOH (cat), MeOH, rt, O/N, 80% yield; (b) H3PO4, DMSO, rt, 3h, 78% yield; (c)
ArMgBr, THF or ether, rt, 3h, 77–78% yield; (d) 1:2aq TFA–CHCl 3, rt, 0.5–4h, 24–98% yield; (e) CeCl3ÆH2O/MeOH, NaBH4, rt, 0.5–4h, 84–100%
yield.
tection in these systems. With an efficient route to the
cyclic ketal derivative 8 in hand, the secondary hydroxyl
group was oxidised via Pfitzner and Moffatt conditions16
to provide the ketone derivative 9 in good yield. Aryl-
ation of 9 with phenylmagnesium bromide and 3,4-
methylenedioxyphenylmagnesium bromide afforded the
6-arylhydroxy derivatives 10 and 11 respectively, in
good yield.
the cyclic ketal ring positioned in part below the bicyclic
tropane ring. This conformation blocks the concave face
of the tropane ring, indicating that the large phenyl
Grignard reagent would attack solely from the top face
of the tropane skeleton, leading to formation of only the
6b-aryl isomers (10 and 11). In confirmation of this,
1
NOESY 1D H NMR experiments on 10 revealed the
hydroxyl proton to have a NOE interaction with the
H5, H4 and H2protons (see Supplementary material),
whereas the aromatic ortho-protons displayed NOE
interactions with only the H5 and H7 protons. This
clearly indicated that the phenyl ring functionality was
exo to the tropane skeleton and the hydroxyl group
was endo. The same orientation would be expected for
11.
In order to determine the stereochemistry of the aryl
ring at the 6-position, molecular modelling data for 9
(using conformational searching and geometry optimi-
sation at the molecular mechanics level in the SPAR-
ꢁ
TAN program17) was investigated. The lowest energy
conformer of 9 was that shown in Figure 3 (left), with

5642
S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
tion of the secondary 6-hydroxyl group of 20 under
Pfitzner and Moffatt16 conditions provided ketone 21
in reasonable yield. The ketone derivative 21 was then
treated with phenylmagnesium bromide and 3,4-methyl-
enedioxyphenylmagnesium bromide to afford 22 and 23,
respectively, in good yields. As with the dioxolane deriv-
ative 9, assessment of the lowest energy conformer of the
dimethyl ketal derivative 21 suggested that Grignard
reagent attack on the ketone would occur preferentially
from the exo-face (data not shown). Target ligands 1, 2
and 3 were then potentially accessible from 22 or 23.
In an attempt to remove the dimethyl ketal protecting
group, 22 was treated with 50% aqueous TFA in chloro-
form,20 producing a nonseparable mixture of the ketone
14 (minor isomer) and its cyclic hemi-ketal 26 (major
isomer) (Scheme 2) as assigned by 13C NMR spectro-
scopy (a weak signal at d 203.1 was ascribed to the C3
carbonyl of 16, and a signal at d 103.6 to the C3 carbon
in the cyclic hemi-ketal 26). Treatment of the methylen-
edioxyphenyl derivative 23 with TFA–chloroform pro-
duced two separable isomers, ketone derivative 15 (the
signal ascribed to the C3 carbonyl appeared in the
13C NMR at d 204.2) and cyclic hemiketal derivative
27 (on the basis of the signal for the C3 carbon at
d103.6). The ring system embodied in the new cyclic
hemi-ketal is that of the tropane alkaloid deoxynorsco-
poline. The related 7-hydroxylated deoxyscopoline com-
pound, oscine (scopoline), is a direct product of the
hydrolysis of scopolamine.21 The synthesis of both deo-
xynorscopoline and oscine have been investigated from
nonalkaloid sources.22
Figure 3. Computer-based (SPARTAN) molecular models of the lowest
energy conformations of 9 (left) and 10 (right), indicating the favoured
exo-aryl functionality in 10.
With derivatives 10 and 11 synthesised, six target and
intermediate compounds, for structure-pharmacological
activity relationship assessment were accessible, namely
1, 3, 12, 13, 16 and 17 (Fig. 4). Direct hydrolysis of
the carbamate protecting group in derivatives 10 and
11 would yield derivatives 12 and 13. Removal of the
cyclic ketal from 10 and 11 would provide ligands 14
and 15, which may be either hydrolysed to afford ligands
16 and 17, or reduced to afford the b-hydroxylic deriva-
tives 18 and 19, which in turn could be converted to tar-
get derivatives 1 and 3, and the methylenedioxy
functionality could be unmasked to reveal the catechol
2. A mild, neutral and high-yielding method for the
transformation of cyclic ketals to their parent ketones
is the use of cerium trichloride heptahydrate and sodium
iodide under refluxing conditions.18 However, extensive
treatment of 10 under such conditions failed to yield any
of the desired ketone 14. With few suitably mild and
neutral methods for cyclic ketal removal available, an
alternative acyclic, dimethyl ketal protecting group
was investigated. Compound 6 was therefore treated
with trimethylorthoformate and p-toluenesulfonic
acid,19 resulting in ketal formation as well as silyl ether
cleavage to afford 20 in good yield (Scheme 2). Oxida-
Unreported preliminary qualitative adrenergic ligand
pharmacophore work we have undertaken upon 3,6,6-
trisubstituted aryl tropane derivatives (such as 1–3) sug-
gested that the stereochemistry of the 3-hydroxyl substi-
tutent may be important; in particular the b-
stereochemistry may impart greater activity at the al-
pha1-adrenergic receptors than the a-stereochemistry.
We therefore proceeded with the preparation of b-
CO2CH2CCl3
CO2CH2CCl3
CO2CH2CCl3
N
N
N
Ar
Ar
Ar
O
OH
OH
OH
OH
O
O
10 Ar = Phenyl
11 Ar = 3,4-(OCH2O)-Ph
14 Ar = Phenyl
15 Ar = 3,4-(OCH2O)-Ph
18 Ar = Phenyl
19 Ar = 3,4-(OCH2O)-Ph
H
N
H
N
H
N
Ar
Ar
Ar
O
OH
OH
OH
OH
O
O
12 Ar = Phenyl
16 Ar = Phenyl
1 Ar = Phenyl
13 Ar = 3,4-(OCH2O)-Ph
17 Ar = 3,4-(OCH2O)-Ph
3 Ar = 3,4-(OCH2O)-Ph
Figure 4. Route to target derivatives from 10 and 11.

S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
5643
hydroxylic derivatives, via the selective reduction of ke-
tones 14 and 15 (and their hemi-ketal derivatives).
Reduction of the ketone/hemi-ketal mixture 14/26 with
cerium chloride heptahydrate and sodium borohydride
in methanol afforded the b-hydroxy derivative 1823–25
(Scheme 2). Compound 15 was also treated with cerium
chloride heptahydrate and sodium borohydride in meth-
anol to selectively afford the b-hydroxy derivative 19
(Scheme 2). The axial H3 proton of 19 was represented
by two very close but separate peaks: one at d 3.94
(0.75H integration) and the other at d 4.07 (0.25H inte-
gration), indicative of either carbamate rotamers or slow
conformational interchange in this case. The latter was
supported by the NOESY 1D NMR, which indicated
that the peak at d 3.94 displayed interactions with H2,
H4, H7ax and the tertiary hydroxyl proton, while the
H3 peak at d 4.07 displayed interactions with only
H2ax/eq and H4ax/eq. This indicated that the tropane
was partially existing in the boat conformation, as a re-
sult of H-bonding between the 3-hydroxyl and the car-
bamate carbonyl group (H3 in this conformation
would then be equatorially disposed, and would be too
far from the 6-hydroxy and H7ax to have a NOE inter-
action). The equatorial conformation of H3 is reflected
in the H2/H4 equatorial–axial coupling constant of
5.4Hz, whilst the equatorial–equatorial coupling con-
stant was too small to be seen.
catechol adrenaline mimic, difficulties with the deprotec-
tion of the methylenedioxy group hindered the prepara-
tion of compound 2 and its derivatives. The synthesis of
these catechol derivatives via an alternate method is cur-
rently being addressed.
2.2. Evaluation of 3,6,6-trisubstituted derivatives at
alpha1-adrenergic receptors
Compounds 1, 3, 12, 13, 28, 29, 30 and 31 (as the hydro-
chloride salts) were assessed for ligand binding charac-
teristics upon membrane-expressed a1A-, a1B- and a1D
ARs in a series of radioligand binding studies using
125I]-HEAT. Affinity data (IC50, lm) is given in Table
-
[
1. Whilst the ligands exhibited poor binding affinity
(IC50 > 300lM) on both the a1A-AR and a1B-AR, com-
pounds 1, 12, 29 and 30 did exhibit some selectivity for
the a1D-AR. Of these compounds, 12 exhibited the high-
est affinity (3.8lM) and selectivity (> 25-fold) for the
a
1D-AR, however it displayed only 5.8% of the affinity
of the endogenous ligand, adrenaline, for the a1D-AR.
Although the affinity of compound 12 for the a1D-AR
does not compare to other reported ligands, which dis-
play nanomolar affinities,26,27 it does provide promising
selectivity. The bicyclic tropane skeleton is worth pursu-
ing in the search for a new class of a1D-selective adren-
ergic receptor ligands.
Removal of the carbamate protecting groups of deriva-
tives 10, 11, 22, 23, 26, 27, 18 and 19 utilising zinc in ace-
tic acid12 afforded the nortropane derivatives 1, 3, 12,
13, 28, 29, 30 and 31, in moderate to quantitative yields
(Scheme 3). Treatment of the dimethyl ketal derivatives
22 and 23 with zinc in acetic acid led not only to removal
of the carbamate moiety, but also to the loss of one of
the methoxy substituents, resulting in the hemi-ketal
derivatives 30 and 31. Although the unmasking of the
methylendioxy functionality was desired to provide the
3. Conclusions
Aryl nortropane derivatives 1, 2 and 3 were designed as
conformationally restricted folded mimics of the endog-
enous adrenergic receptor ligand adrenaline. A range of
3,6,6-trisubstituted tropane derivatives, based upon
6b-phenyltropane-3b,6a-diol (1), including some novel
related tricyclic hemi-ketal and tricyclic ketal com-
pounds, have been synthesised utilising stereocontrolled
O
O
O
O
C O CH2CCl3
N
C O CH2CCl3
N
C O CH2CCl3
N
C O CH2CCl3
N
Ar
Ar
Ar
Ar
OCH3
OH
O
OH
OH
OH
O
O
OH
OCH3
H
10 Ar = Phenyl
11 Ar = 3,4-(OCH O)-Ph
22 Ar = Phenyl
23 Ar = 3,4-(OCH O)-Ph
26 Ar = Phenyl
27 Ar =3,4-(OCH O)-Ph
18 Ar = Phenyl
19 Ar = 3,4-(OCH O)-Ph
2
2
2
2
H
N
H
N
H
N
H
N
Ar
Ar
Ar
Ar
OCH3
O
OH
O
OH
OH
O
O
OH
H
12 Ar = Phenyl
13 Ar = 3,4-(OCH O)-Ph
30 Ar = Phenyl
31 Ar = 3,4-(OCH O)-Ph
28 Ar = Phenyl
29 Ar = 3,4-(OCH O)-Ph
1 Ar = Phenyl
3 Ar = 3,4-(OCH O)-Ph
2
2
2
2
Scheme 3. Reagents and conditions: zinc, acetic acid, 24h, 40ꢂC, 30–85% yield.

5644
S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
syntheses. Novel microwave reactions aided in the opti-
misation of the synthesis. The compound 6b-phenyl-8-
azabicyclo[3.2.1]octan-3-spiro-20-(10, 30-dioxolane)-6-ol
(12) exhibited > 25-fold selectivity for the a1D-AR.
Given the lack of selective a1D-AR ligands available,
compound 12 and the tropane class of compounds
provides a new lead for the development of selective
a
1D-AR ligands.
4. Experimental
4.1. General chemistry methods
Microwave reactions were performed in a Milestone
Ethos Sel Microwave Solvent Extractor, employing
Easywave software, and using internal reaction temper-
ature control. Sealed Teflon reaction vessels were used,
and were washed with concentrated nitric acid between
uses. Melting point determinations were carried out on
a Griffin melting point apparatus. Low resolution chem-
ical ionisation (isobutane, CI+) mass spectra were ob-
tained on a Shimadzu QP-5000 mass spectrometer by
a direct insertion technique with an electron beam of
70eV. High-resolution mass spectra (HRMS) (methane,
CI+ and EI+) were determined on a VG Autospec spec-
trometer using PFK (perfluorokerosene) as the internal
standard. The m/z values are stated with their peak
intensities as a percentage in parentheses. Proton and
carbon nuclear magnetic resonance (NMR) spectra were
obtained on a Varian Unity 300MHz or a Varian Mer-
cury 300MHz spectrometer. Spectra were recorded in
deuterated chloroform, unless otherwise specified, and
referenced to the residual nondeuterated solvent signal.
Chemical shifts (d) in ppm were measured relative to
the internal standard. Analytical thin layer chromato-
graphy (TLC) was carried out on Merck Silica gel 60
F254 pre-coated aluminium plates with a thickness of
0.2mm. Chromatography refers to column chromatog-
raphy, performed under ꢀflashꢁ conditions on Merck Sil-
ica gel 60 (230–400mesh). Chromatography solvent
mixtures were measured by volume, and are reported
in parentheses. The Rf values given refer to the determi-
nation of a sample on TLC in the same solvent as noted
for the chromatography. All compounds were of greater
1
than 95% purity based on H NMR and TLC analysis.
Organic extracts were dried with anhydrous sodium sul-
fate, and the solvent was removed under reduced pres-
sure (in vacuo) with a Buchi rotary evaporator.
¨
Anhydrous solvents were purified and dried according
to Perrin and Armarego28 and distilled immediately be-
fore use. Other solvents used were AR grade, and were
used as received, with the exception of dichloromethane
(DCM) and hexane, which were LR grade and were dis-
tilled before use. Starting materials and reagents were
purchased from Sigma Aldrich Pty Ltd and were used
as received.
4.2. Synthesis
4.2.1. 6b-O-tert-Butyldimethylsilyl-8-methyl-8-azabicy-
clo[3.2.1]octan-3-one
(0.554g, 3.57mmol) was dissolved in anhydrous DCM
(5).
6b-Hydroxytropan-3-one

S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
5645
(20mL) and cooled to 0ꢂC under nitrogen with stirring.
The base 2,6-lutidine (0.833mL, 7.14mmol) and tert-
butyldimethylsilyltrifluoromethanesulfonate (1.23mL,
5.35mmol) were then added dropwise consecutively via
syringe, and stirring was continued for 3h as the solu-
tion was allowed to warm to room temperature. The
reaction was quenched by the addition of water
(40mL) and saturated aqueous sodium hydrogen car-
bonate (10mL). Extraction with DCM (100mL), drying
and concentration in vacuo yielded a yellow liquid.
Chromatography (ethyl acetate; Rf 0.31) provided the
ketone 5 (C14H27NO2Si) as a pale yellow oil (0.83g,
to microwave radiation for 2min warming to 100 ꢂC,
followed by 18min at 100ꢂC. The reaction mixture
was allowed to cool, then taken up in ethyl acetate
(50mL) and water (50mL) and separated. The aqueous
fraction was extracted with ethyl acetate (3 · 50mL) and
combined organic extracts were washed with sodium
chloride (satd) (50mL), water (50mL) dried and concen-
trated in vacuo to yield a brown oil. Chromatography
(1:4 ethyl acetate–hexane; Rf 0.46) provided
6
(C16H26NO4SiCl3) as a white solid (0.796g, 60% yield).
All spectral and melting point data agreed with that
previously determined for 6.
1
86% yield). H NMR (d): 0.04 (6H, s, (CH3)3Si); 0.87
(9H, s, (CH3)3); 2.01–2.06 m (2H, m, H2e, H4e); 2.13
(2H, dd, H2a, H4a, JH2a,2 e = JH4a,4e = 15.9); 2.63 (3H,
s, N-CH3); 2.57–2.65 (2H, m, H7, H70); 3.28 (1H, d,
4.2.3. 6b-O-tert-Butyldimethylsilyl-8-(2,2,2-Trichloroeth-
oxycarbonyl)-8-azabicyclo[3.2.1]-3-spiro-20-(10,30-dioxo-
lane)-octane (7). To a stirred solution of ethanediol
(0.27mL, 4.91mmol) and anhydrous DCM (15mL) un-
der nitrogen was added 16 (0.96g, 2.23mmol). To this
mixture was added chlorotrimethylsilane (1.25mL,
9.82mmol) and the mixture was heated at reflux for
72h. A 5% aqueous solution of sodium hydrogen car-
bonate (20mL) was added and the mixture extracted
with diethyl ether (3 · 100mL). The combined organic
extracts were washed with sodium chloride (satd)
(100mL), water (100mL), dried and concentrated in va-
cuo to yield a pale yellow oil. Chromatography (1:6
ethyl acetate–hexane; Rf 0.69) provided 17 (C181H30NO5-
SiCl3) as a pale yellow oil (0.90g, 86% yield). H NMR
(d): 0.06 (6H, s, (CH3)3Si); 0.86 (9H, s, (CH3)3); 1.67–
1.90 (2H, m, H2e, H4e); 1.97–2.30 (1H, m, H2a(H4a));
2.26–2.42 (1H, m, H4a(H2a)); 2.46–2.75 (2H, m, H7a,
H7e); 3.83 (1H, t, OCH, J = 6.3); 3.91–3.99 (1H, m,
OCH); 4.09–4.21 (2H, m, OCH2); 4.39 (1H, t, H1,
J = 5.7, 7.2); 4.47–4.59 (1H, m, H5); 4.62–4.74 (2H, m,
CH2); 4.82–4.98 (1H, m, H6). 13C NMR (d): 4.7
((CH3)2Si); 10.1 ((CH3)3CSi); 25.8 ((CH3)3); 39.5
(40.1*) (CH2, C4); 45.5 (46.0*) (CH2, C2); 48.5 (48.9*)
(CH2, C7); 53.0 (53.5*) (CH, C1); 62.5 (62.6*) (CH,
C5); 63.5 (OCH2); 64.5 (OCH2); 74.0 (74.7*) (CH, C6);
74.8 (75.4*) (CH2CCl3); 95.8 (CCl3); 106.7 (C3); 151.7
(152.0*) (NC@O). MS (CI+): m/z 474, 476, 478
(MH+); 416, 418, 420; 342, 344, 346; 327; 300; 177.
HRMS (CI+): Found: 474.1037; Required: 474.0952
for C18H31NO5Si35Cl3.
H1, J = 4.8); 3.55 (1H, ddd, H5, JH5,4e = 1.5, JH5,6
4.2,JH5,4a = 6.0); 4.08 (1H, dd, H6, JH6,7e = 3.6,
=
JH6,5 = 6.9). 13C NMR (d): ꢀ 4.7 ((CH3)2Si); 18.1
((CH3)3CSi); 25.9 ((CH3)3); 38.2(N–CH ); 41.3 (CH2,
3
C4); 44.4 (CH2, C2); 46.3 (CH2, C7); 60.8 (CH, C1);
69.4 (CH, C5); 79.6 (CH, C6); 208.4 (C@O, C3). MS
(CI+): m/z 270 (M + 1, 100%); 256 (39%); 224 (26%).
HRMS (CI+): Found: 270.1903; Required: 270.1889
for C14H28NO2Si.
4.2.2. 6-exo-O-tert-Butyldimethylsilyl-8-(2,2,2-trichloro-
ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-one (6). The
base 5 (1.33g, 4.94mmol), 2,2,2-trichloroethyl chloro-
formate (0.748mL, 5.43mmol) and anhydrous potas-
sium carbonate (0.683g, 4.94mmol) were heated at
reflux in anhydrous benzene under nitrogen for 4days.
The benzene was then azeotroped with methanol, and
the crude reaction mixture taken up in ethyl acetate
(100mL) and water (100mL) and separated. The aque-
ous fraction was extracted with ethyl acetate
(3 · 100mL) and combined organic extracts were
washed with sodium chloride (satd) (100mL), water
(100mL), dried and concentrated in vacuo to yield a
brown oil which crystallised upon standing. Chromatog-
raphy (1:4 ethyl acetate–hexane; Rf 0.46) provided 6
(C16H26NO4SiCl3) as a white solid (1.80g, 85% yield).
Mp: 68–70ꢂC. 1H NMR (d): 0.05 (6H, s, (CH3)2Si);
0.86 (9H, s, (CH3)3); 2.04–2.13 (2H, m, H2e, H4e);
2.40 (2H, dd, H2a, H4a, JH2a,2 e = JH4a,4e = 16.2);
2.65–2.74 (2H, m, H7a, H7e); 4.18 (1H, dd, H1,
JH1,2a = 12.6, JH1,2e = 5.4); 4.39 (1H, dd, H5,
JH5,4e = 5.7, JH5,4a = 6.9); 4.67–4.77 (2H, m, CH2); 4.92
(1H, dd, H6, J = 11.7, 14.1). 13C NMR (d): ꢀ 4.7
((CH3)2Si); 18.1 ((CH3)3CSi); 25.8 ((CH3)3); 41.4
(42.0*) (CH2, C4); 45.5 (46.0*) (CH2, C2); 48.5 (48.9*)
(CH2, C7); 53.0 (53.2*) (CH, C1); 62.5 (62.5*) (CH,
C5); 74.7 (75.4*) (CH2CCl3); 74.8 (75.4*) (CH, C6);
95.8 (CCl3); 152.0 (NC@O); 206.0 (C@O, C3). MS
(CI+): m/z 430, 432, 434 (MH+); 396/398 (MH+ ꢀ Cl);
372, 374, 376; 298, 300, 302; 282. HRMS (CI+): Found:
430.0747; Required: 430.0775 for C16H26NO4Si35Cl3.
4.2.4.
8-(2,2,2-Trichloroethoxycarbonyl)-8-azabicyclo-
[3.2.1]octan-3-spiro-20-(10,30-dioxolane)-6b-ol (8). To a
stirred solution of 7 (0.13g, 0.274mmol) in anhydrous
THF (5mL) under nitrogen at 0ꢂC was added tetrabu-
tylammonium fluoride (1M in THF). The reaction was
stirred at room temperature for 3h, excess ammonium
chloride was added and the mixture stirred for 10min.
The mixture was filtered and the THF was removed in
vacuo. The residue was extracted with ethyl acetate
(50mL), washed with water (3 · 50mL), dried and con-
centrated in vacuo to yield a yellow oil. Chromatogra-
phy (1:1 ethyl acetate–hexane; Rf 0.30) provided 8
(C12H16NO5Cl3) as a colourless oil (0.068g, 69% yield).
1H NMR (d): 1.73–2.15 (2H, m, H2e, H4e); 2.32–2.56
(2H, m, H2a, H4a); 2.67–2.76 (2H, m, H7a, H7e); 3.82
(2H, dd, OCH2, J = 6.0, 6.0); 3.96 (2H, dd, OCH2,
J = 6.3, 6.3); 4.17–4.26 (1H, m, H1); 4.48 (1H, d, H5,
J5,6 = 6.3); 4.55–4.70 (2H, m, CH2); 4.88–5.02(1H, m,
Microwave Method: To 5 (0.83g, 3.08mmol) in anhy-
drous acetonitrile (15mL) under argon was added
2,2,2-trichloroethyl
chloroformate
(0.467mL,
3.39mmol) and anhydrous potassium carbonate
(0.426g, 3.08mmol). The reaction mixture was exposed

5646
S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
H6). 13C NMR (d): 38.4 (40.9*) (CH2, C4); 45.0 (45.5*)
(CH2, C2); 48.3 (48.9*) (CH2, C7); 52.9 (53.6*) (CH,
C1); 62.2 (62.5*) (CH, C5); 63.5 (OCH2); 64.5 (OCH2);
73.5 (74.3*) (CH, C6); 74.6 (74.7*) (CH2CCl3); 95.8
(CCl3); 106.5 (C3); 152.2 (NC@O). MS (CI+): m/z 360,
362, 364 (MH+); 316, 318, 320 (MH+ ꢀ CH2CH2O);
298, 300, 302 (MH+ ꢀ H2O); 282, 284 (MH+ ꢀ Cl).
HRMS (CI+): Found: 360.0153; Required: 360.0173
for C12H17NO5Si35Cl3.
stirring. Phenylmagnesium bromide (3M in diethyl
ether) (0.558mL, 1.637mmol) was added dropwise and
stirring continued for 3h. The reaction mixture was ta-
ken up in water (20mL) and extracted with diethyl ether
(3 · 50mL). The combined organic extracts were
washed with sodium chloride (satd) (50mL), water
(50mL), dried and concentrated in vacuo to yield a pale
yellow oil. Chromatography (1:2ethyl acetate–hexane;
Rf 0.65) provided 10 (C18H20NO5Cl3) as a white solid
(0.280g, 77% yield). 10 was recrystallised from ethyl
acetate/hexane. Mp: 110–112ꢂC. 1H NMR (d): 2.00
(1H, dd, H7a, J7a,7e = 8.4, J7a,5 = 7.5); 2.14–2.23 (2H,
m, H2e, H4e); 2.36–2.46 (2H, m, H2a, H4a); 2.68–2.80
(1H, m, H7e); 3.97 (2H, dd, OCH2, J = 6.3, 1.5); 4.02–
4.18 (2H, m, OCH2); 4.29 (1H, br s, OH); 4.55 (1H,
dd, H1, J1,2 = 10.8, J1,7e = 8.4); 4.70–4.92(H2, m,
CH2); 5.02(1H, d, H5, J = 2.7); 7.20–7.35 (3H, m,
ArH · 3); 7.52(2H, t, ArH · 2, J = 7.2). 13C NMR (d):
36.9 (37.7*) (CH2, C7); 40.5 (41.4*) (CH2, C4); 44.9
(45.8*) (CH2, C2); 52.7 (52.8*) (CH, C1); 62.8 (63.1*)
(CH, C5); 63.8 (OCH2); 64.7 (OCH2); 74.4 (74.5*)
(CH2CCl3); 79.8 (80.3*) (C6); 95.5 (95.6*) (CCl3);
107.0 (C3); 123.9, 124.0, 125.2, 126.7, 128.1 (ArCH · 5);
150.8 (151.1*) (NC@O). MS (CI+): m/z 436, 438, 440
(MH+, 436, 29%); 418, 420, 422 (MH+ ꢀ H2O, 418,
100%).
Microwave method: To a solution of 6 (0.680g,
1.578mmol) in anhydrous acetonitrile (10mL) under
an argon stream was added ethanediol (0.194mL,
3.472mmol)
followed
by
chlorotrimethylsilane
(0.878mL, 6.944mmol). The reaction mixture was ex-
posed to microwave radiation: warming to 80ꢂC for
2min, followed by heating at 80 ꢂC for 23min. The reac-
tion mixture was allowed to cool, then diluted with 5%
aqueous sodium hydrogen carbonate (20mL) and ex-
tracted with diethyl ether (3 · 50mL). The combined or-
ganic fractions were washed with water (2 · 50mL),
dried (sodium sulfate) and concentrated in vacuo to yield
a yellow oil. Chromatography (1:1 ethyl acetate–hexane;
Rf 0.43) yielded 8 (C12H16NO5Cl3) as a colourless oil
(0.470g, 83% yield). All spectral data agreed with that
previously determined for 8.
4.2.5.
8-(2,2,2-Trichloroethoxycarbonyl)-8-azabicyclo-
4.2.7. 8-(2,2,2-Trichloroethoxycarbonyl)-6b-(3,4-methyl-
enedioxyphenyl)-8-azabicyclo[3.2.1]octan-3-spiro-20-(10,30-
dioxolane)-6a-ol (11). To a stirred solution of 9 (0.090g,
0.251mmol) in anhydrous diethyl ether (4mL) under
nitrogen was added 3,4-methylenedioxyphenylmagne-
sium bromide (1M in THF:toluene (50:50)) (0.301mL,
0.301mmol) dropwise, and stirring continued for 3h.
The reaction mixture was taken up in water (10mL)
and extracted with diethyl ether (3 · 25mL). The com-
bined organic extracts were washed with sodium chlo-
ride (satd) (25mL), water (25mL), dried and
concentrated in vacuo to yield a pale yellow oil. Chro-
matography (1:2ethyl acetate–hexane; Rf 0.45) provided
11 (C19H20NO7Cl3) as a colourless oil (0.90g, 75%
yield). 1H NMR (d): 1.94–2.44 (5H, m, H2a, H2e,
H4a, H4e, H7a); 2.63–2.76 (1H, m, H7e); 3.96–4.00
(2H, m, OCH2); 4.05–4.18 (2H, m, OCH2); 4.23 (1H,
dd, OH, J = 3.6, 9.6); 4.53 (1H, dd, H1, J = 11.4, 9.9);
4.70–4.90 (2H, m, CH2); 4.99 (1H, s, H5); 5.92(2H, s,
OCH2O); 6.70–6.80 (1H, m, ArH); 6.85–6.98 (1H, m,
ArH); 7.05 (1H, dd, ArH, J = 2.1, 8.7). 13C NMR (d):
36.9 (37.7*) (CH2, C7); 40.4 (41.4*) (CH2, C4); 45.0
(45.8*) (CH2, C2); 52.6 (52.8*) (CH, C1); 53.1 (53.3*)
(CH, C5); 63.9 (OCH2); 64.7 (OCH2); 74.5 (74.6*)
(CH2CCl3); 79.8 (80.4*) (C6); 95.5 (95.6*) (CCl3);
100.8 (OCH2O); 105.4 (ArCH); 107.0 (C3); 107.6
(ArCH); 117.1 (ArCH); 142.3, 146.1, 147.5 (ipso C
· 3); 150.8 (151.2*) (NC@O). HRMS (CI+): Found:
483.0247; Required: 483.0246 for C19H21NO735Cl37Cl2.
[3.2.1]octan-3-spiro-20-(10,30-dioxolane)-6-one (9). The
alcohol 8 (0.46g, 1.28mmol) was dissolved in a stirred
solution of anhydrous dimethylsulfoxide (5mL) and dic-
yclohexylcarbodiimide (0.79g, 3.83mmol). Phosphoric
acid (anhydrous) (0.063g, 0.64mmol) in anhydrous
dimethylsulfoxide (1mL) was added dropwise and the
mixture stirred at room temperature for 3h. Ethyl ace-
tate (30mL) was added, followed by a solution of oxalic
acid (0.25 g) in methanol (10mL) and stirring continued
for 30min. The precipitated dicyclohexylurea was re-
moved by filtration, washed with ethyl acetate
(100mL) and the solution was extracted with aqueous
sodium hydrogen carbonate (satd) (50mL), water
(50mL), dried and concentrated in vacuo to yield an
off-white semi-solid. Chromatography (1:3 ethyl ace-
tate:hexane; Rf 0.40) provided 9 (C12H14NO5Cl3) as a
white solid (0.324g, 71% yield). Mp: 87–90ꢂC. 1H
NMR (d): 1.90 (1H, d, H7e, J7e,7a = 13.5); 2.22–2.42
(2H, m, H2e, H4e); 2.51–2.69 (2H, m, H2a, H4a); 2.89
(1H, m, H7a); 3.88–3.91 (2H, m, OCH2); 3.92–3.97
(2H, m, OCH2); 4.60 (1H, d, H1, J1,2e = 2.1); 4.66–4.91
(2H, m, CH2); 5.03 (1H, br d, H5, J5,6 = 6.0). 13C
NMR (d): 38.9 (39.4*) (CH2, C7); 40.1 (CH2, C4); 42.3
(42.9*) (CH2, C2); 51.4 (CH, C1); 59.7 (60.0*) (CH,
C5); 64.1 (OCH2); 64.7 (OCH2); 74.7 (74.9*) (CH2CCl3);
95.8 (CCl3); 105.9 (C3); 151.8 (NC@O); 202.9 (C@O,
C6). MS (CI+): m/z 360, 362, 364 (MH+); 342, 344,
346 (MH+ ꢀ H2O); 316, 318, 320; 298, 300, 302. HRMS
(CI+): Found: 358.0018; Required: 358.0016 for
C12H15NO535Cl3.
4.2.8. 8-(2,2,2-Trichloroethoxycarbonyl)-6b-hydroxy-3,3-
dimethoxy-8-azabicyclo[3.2.1]-octane (20).
A stirred
4.2.6.
8-(2,2,2-Trichloroethoxycarbonyl)-6b-phenyl-8-
solution of 6 (0.420g, 0.975 mol) in anhydrous methanol
(10mL) was treated with trimethylorthoformate
(0.23mL, 2.083mmol) and p-toluenesulfonic acid mono-
hydrate (0.004g, 0.023mmol) and the resulting solution
azabicyclo[3.2.1]octan-3-spiro-20-(10,30-dioxolane)-6a-ol
(10). The ketone 9 (0.300g, 0.837mmol) was dissolved in
anhydrous diethyl ether (10mL) under nitrogen with

S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
5647
was stirred at room temperature for 16h. The reaction
mixture was treated with diethyl ether (10mL) and
potassium carbonate (0.116 g), filtered through a plug
of florosil and concentrated to yield 20 (C12H19NO5Cl3)
(0.300g, 85% yield) as a pale yellow oil after chromato-
Found:
406.0363;
Required:
406.0380
for
C17H19NO435Cl3 (loss of CH3OH).
4.2.11. 8-(2,2,2-Trichloroethoxycarbonyl)-3,3-dimethoxy-
6b-(3,4-methylenedioxyphenyl)-8-azabicyclo[3.2.1]-octan-
6a-ol (23). Following the method used for 11, 23
(C19H22NO7Cl3) (0.199g, 84% yield) was prepared from
21 (0.177g, 0.491 moles) as a colourless oil after chroma-
1
graphy (ethyl acetate; Rf 0.79). H NMR (d): 1.73-1.77
(1H, m, H7e); 1.84 (2H, dd, H2e, H4e, J = 4.2, 14.4);
1.96-2.00 (1H, m, H2a); 2.12-2.20 (1H, m, H7a); 3.11
(3H, s, OCH3); 3.15 (3H, s, OCH3); 4.08–4.18 (1H, m,
H1); 4.46 (2H, dd, CH2, J = 6.3, 7.8); 4.47 (1H, H5,
J = 7.2); 4.90 (1H, t, H6, J = 11.7). 13C NMR (d): 35.8
(36.4*) (CH2, C2(C4)), 36.5 (37.2*) (CH2, C4(C2));
39.5 (40.0*) (CH2, C7); 47.3 (OCH3); 48.1 (OCH3);
53.1 (53.2*) (CH, C1); 62.0 (62.2*) (CH,C5); 73.2
(74.0*) (C6); 74.5 (74.6*) (OCH2CCl3); 95.5 (CCl3);
98.3 (C3); 151.8 (NC@O). MS (CI+): m/z 362, 364, 366
(MH+); 330, 332, 334 (MH+ ꢀ CH3OH); 312, 314, 316
(MH+ ꢀ H2O); 296, 298; 278, 280. HRMS (CI+):
1
tography (1:4 ethyl acetate–hexane; Rf 0.28). H NMR
(d): 1.92–1.99 (1H, m, H7a); 2.02–2.13 (1H, m, H2e);
2.19–2.30 (m, 1H, H4e); 2.49–2.59 (2H, m, H2a, H4a);
2.68 (1H, ddd, H7e, J = 8.4, 14.4, 15.3); 3.22 (3H, s,
OCH3); 3.32(3H, s, OCH ); 4.21 (1H, dd, H1, J = 3.3,
3
12.3); 4.43–4.50 (1H, m, H5); 4.68–4.89 (2H, m, CH2);
5.28 (1H, s, OH) (exchangeable with D2O) 5.92(2H, s,
OCH2O); 6.72(1H, dd, ArH, J = 1.8. 8.4); 6.93–6.98
(1H, m, ArH); 7.05 (1H, dd, ArH, J = 1.8, 8.4). 13C
NMR (d): 35.2(35.7*) (CH , C4), 36.1 (36.5*) (CH2,
2
Found:
363.0221;
Required:
363.0207
for
C2); 45.1 (46.0*) (CH2, C7); 47.5 (47.8*) (OCH3); 48.1
(OCH3); 52.2 (52.4*) (CH, C1); 62.8 (63.0*) (CH, C5);
74.5 (74.6*) (OCH2CCl3); 79.5 (80.2*) (CH, C6); 95.5
(CCl3); 99.3 (C3); 100.8 (OCH2O); 105.4, 107.6
(ArCH · 2); 117.0 (ArCH); 142.1, 146.1, 147.5 (ipso
C · 3); 151.1 (NC@O). MS (CI+): m/z 390, 392, 394;
360, 362, 364; 342, 344, 346; 328, 330, 332; 294, 296.
HRMS (EI+): Found: 449.0157; Required: 449.0200
for C18H18NO635Cl3 (loss of CH3OH).
(C12H19NO535Cl237Cl).
4.2.9. 8-(2,2,2-Trichloroethoxycarbonyl)-3,3-dimethoxy-
8-azabicyclo[3.2.1]-octan-6-one (21). Following the
method used for 9, 21 (C12H17NO5Cl3) (0.490g, 71%
yield) was prepared from 20 (0.700g, 1.93 moles) as a
colourless oil which crystallised to a white solid after
chromatography (1:2ethyl acetate–hexane; Rf 0.74).
Mp: 62–63ꢂC. 1H NMR (d): 1.75 (1H, dd, H2e,
J = 3.9, 13.8); 2.03–2.19 (2H, m, H4e, H7e); 2.42–2.65
(3H, m, H2a, H4a, H7a); 3.04 (3H, s, OCH3); 3.16
(3H, s, OCH3); 4.21 (1H, m, H1); 4.72–4.88 (3H, m,
4.2.12. 8-(2,2,2-Trichloroethoxycarbonyl)-6b-phenyl-8-
azabicyclo[3.2.1]-3-oxo-octan-6-ol (14) and 4-(2,2,2-tri-
chloroethoxycarbonyl)-6ab-phenyl-2,5-methano-hexahydro-
2H-furo[3,2-b]pyrrol-6aa,2b-diol (26). A stirred solution
of 22 (0.103g, 0.235mmol) in a 2:1 mixture of chloro-
form:trifluoroacetic acid (50% aq) (4mL) was heated
at reflux for 20h. The cooled solution was poured onto
chloroform, separated, and the organic layer washed
with water (5mL), dried and concentrated in vacuo to
yield a pale yellow oil. Chromatography (1:4 ethyl ace-
tate:hexane; Rf 0.19) yielded a colourless oil (0.090g,
98% yield), which proved to be an inseparable mixture
of 14 (C16H16NO4Cl3) and 26 (C16H16NO4Cl3). 1H
NMR (d): 1.93 (1H, d, H7a, J = 11.4); 2.02–2.19 (5H,
m, H2e, H4e, H7e, H2a, H4a); 3.97 (1H, br s, OH);
4.56 (1H, s, H1); 4.72–4.88 (3H, m, CH2, H5); 7.26–
7.43 (5H, m, ArH · 5); 13C NMR (d): 38.4 (38.5*)
(CH2, C4), 44.6 (44.9*) (CH2, C2); 45.3 (45.6*) (CH2,
C7); 55.4 (55.8*) (CH, C1); 65.7 (65.7*) (CH, C5); 74.6
(74.9*) (OCH2CCl3); 88.4 (89.1*) (C6); 95.5 (95.6*)
(CCl3); 103.6 (103.7*) (C3); 124.7, 124.8, 127.6, 128.3,
128.5 (ArCH · 5); 140.1 (140.2*) (ipso C); 150.6
(151.0*) (NC@O); 203.1 (C@O, C3). MS (CI+): 392,
394, 396 (MH+); 374, 376, 378 (MH+ ꢀ H2O); 358,
360, 362; 340, 342, 344; 314, 316, 318; 218; 200.
H5, CH2). 13C NMR (d): 36.2(36.8*) (CH , C4), 36.9
2
(37.6*) (CH2, C2); 42.7 (43.1*) (CH2, C7); 47.4
(OCH3); 47.7 (OCH3); 51.4 (51.8*) (CH, C1); 59.3
(60.3*) (CH,C5); 74.7 (OCH2CCl3); 95.2( CCl3); 98.3
(C3); 151.4 (NC@O); 203.0 (C@O, C6). MS (CI+): m/z
360, 362, 364 (MH+); 342, 344, 346 (MH+ ꢀ H2O);
328, 330, 332 (MH+ ꢀ CH3OH); 294, 296. HRMS
(CI+): Found: 359.0103; Required: 359.0094 for
(C12H18NO535Cl3).
4.2.10. 8-(2,2,2-Trichloroethoxycarbonyl)-3,3-dimethoxy-
6b-phenyl-8-azabicyclo[3.2.1]-octan-6a-ol (22). Follow-
ing the method used for 10, 22 (C18H22NO5Cl3)
(0.293g, 88% yield) was prepared from 21 (0.273g,
0.757 moles) as a colourless oil after chromatography
(1:4 ethyl acetate–hexane; Rf 0.42),which crystallised to
a white solid upon standing. Mp: 100–101ꢂC. 1H
NMR (d): 1.97 (1H, dd, H7a, J = 3.9, 15.0); 2.02–2.15
(2H, m, H2e, H4e); 2.22–2.31 (1H, m, H2a(H4a));
2.51–2.61 (1H, m, H4a(H2a)); 2.69–2.80 (1H, m, H7e);
3.23 (3H, s, OCH3); 3.33 (3H, s, OCH3); 4.27 (1H, dd,
H1 J = 4.2, 5.4); 4.46–4.52 (1H, m, H5); 4.68–4.89
(2H, m, CH2); 7.19–7.36 (3H, m, ArH · 3); 7.49–7.54
(2H, m, ArH · 2). 13C NMR (d): 35.3 (35.7*) (CH2,
C4), 36.1 (36.5*) (CH2, C2); 45.1 (46.0*) (CH2, C7);
47.8 (OCH3); 48.1 (OCH3); 52.3 (52.5*) (CH, C1); 62.5
(62.8*) (CH, C5); 74.4 (74.6*) (OCH2CCl3); 79.5
(80.1*) (CH, C6); 95.5 (CCl3); 99.3 (C3); 124.0, 124.1,
126.7, 128.1, 128.3 (ArC · 5); 147.8 (ipso C); 150.8
(151.1*) (NC@O). MS (CI+): m/z 406, 408, 410
(MH+ ꢀ CH3OH); 372, 374, 376; 354. HRMS (CI+):
4.2.13. 8-(2,2,2-Trichloroethoxycarbonyl)-6a-hydroxy-6-
b-(3,4-methylenedioxyphenyl)-8-azabicyclo[3.2.1]octan-3-
one (15) and 4-(2,2,2-trichloroethoxycarbonyl)-6ab-(3,4-
methylenedioxyphenyl)-2,5-methano-hexahydro-2H-furo-
[3,2-b]pyrrol-6aa,2b-diol (27). A solution of 23 (0.179g,
0.371mmol) in a 2:1 mixture of chloroform:trifluoroace-
tic acid (50% aq) (4mL) was heated at reflux for 20h.
The cooled solution was poured into chloroform, sepa-
rated, and the organic layer washed with water

5648
S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
(2 · 5mL), dried and concentrated in vacuo to yield a
pale yellow oil. Chromatography (1:4 ethyl acetate:hex-
ane) isolated 2products: the ketone derivative 15 and
the hemi-ketal derivative 27. Compound 15
(C17H16NO6Cl3) was isolated as an off-white solid,
which was recrystallised from DCM/diethyl ether
(0.039g, 24% yield); Rf 0.20 (1:4 ethyl acetate–hexane).
Mp: 106–108ꢂC. 1H NMR (d): 2.19–2.28 (1H, m,
H7a); 2.45–2.60 (3H, m, H2e, H4e, H7e); 2.83–2.92
(2H, m, H2a, H4a); 4.72 (1H, dd, H1, J = 4.8, 12.0);
4.94–5.09 (2H, m, CH2); 5.27 (1H, s, H5); 5.98 (2H, s,
OCH2O); 6.31 (1H, dd, OH, J = 2.4, 5.7) (exchangeable
with D2O); 6.77–6.89 (3H, m, ArH · 3). 13C NMR
(d): 44.4, 45.0, 45.2, 45.8 (CH2, C4, C2, C7); 57.1 (CH,
C1, C5); 74.7 (OCH2CCl3); 84.5 (CH, C6); 95.4
(CCl3); 101.3 (OCH2O); 105.8, 108.4 (ArCH · 2); 119.8
(123.3*) (ArCH); 125.0 (ispo C); 145.4, 148.2 (ipso
C · 2); 150.3 (NC@O); 204.2 (C@O). MS (CI+): m/z
436, 438, 440 (MH+, 436, 10%); 418, 420, 422
(MH+ ꢀ H2O, 418, 15%); 384, 386, 388 (384, 20%);
314, 316, 318 (314, 20%); 262 (70%); 244 (100%). HRMS
(EI+): Found: 435.0026; Required: 435.0043 for
C17H16NO6Cl3. 27 (C17H16NO6Cl3) was isolated as a
colourless oil (0.100g, 62% yield); Rf 0.08 (1:4 ethyl ace-
tate–hexane); 1H NMR (d): 1.89 (1H, br m, H7a); 2.06–
2.13 (4H, m, H2e, H4e, H2a, H4a); 2.19–2.31 (1H, m,
H7e); 3.75 (1H, d, OH, J = 3.0); 4.50 (1H, s, H1);
4.70–4.76 (2H, m, CH2CCl3); 4.87 (1H, dd, H5,
J = 6.6, 12.3); 5.95 (2H, s, OCH2O); 6.78 (1H, dd,
ArH, J = 4.5, 8.1); 6.85 (1H, dd, ArH, J = 4.5, 1.5);
6.89 (1H, d, ArH, J = 3.0). 13C NMR (d): 38.5 (38.8*)
(CH2, C4), 44.6 (45.0*) (CH2, C2), 45.1 (45.3*) (CH2,
C7); 55.3 (55.7*) (CH, C1); 65.6 (65.7*) (CH, C5); 74.6
(OCH2CCl3); 88.4 (89.1*) (CH, C6); 95.5 (CCl3); 101.1
(OCH2O); 103.6 (103.7*) (C3); 105.7 (105.8*) (ArCH);
108.0 (ArCH); 118.0 (118.1*) (ArCH); 134.2(ispo C);
146.5, 148.0 (ipso C · 2); 150.8 (NC@O). MS (CI+):
m/z 436, 438, 440 (MH+, 436, 60%); 418, 420, 422
(MH+ ꢀ H2O, 418, 100%); 384, 386, 388 (384, 60%).
HRMS (EI+): Found: 435.0049; Required: 435.0043
for C17H16NO6Cl3.
7.22–7.32 (3H, m, ArH · 3); 7.48–7.54 (2H, m,
ArH · 2). 13C NMR (d): 33.4 (34.1*) (CH2, C4), 38.0
(38.9*) (CH2, C2); 45.8 (46.6*) (CH2, C7); 52.6 (52.9*)
(CH, C1); 62.9 (63.1*) (CH, C3); 63.8 (63.9*) (CH,
C5); 74.4 (74.5*) (OCH2CCl3); 79.7 (80.3*) (C6); 95.5
(CCl3); 124.0, 126.8, 126.8, 128.2, 128.2 (ArCH · 5);
140.1 (ipso C); 151.0 (NC@O). MS (CI+): m/z 394,
396, 398 (MH+, 394, 60%). HRMS (CI+): Found:
395.0274; Required: 395.0272 for C16H18NO435Cl237Cl.
4.2.15. 8-(2,2,2-Trichloroethoxycarbonyl)-6b-(3,4-methyl-
enedioxyphenyl)-8-azabicyclo[3.2.1]octane-3b,6a-diol (19).
To a stirred solution of 0.066M cerium chloride hepta-
hydrate in methanol (3mL) at room temperature was
added 15 (0.049g, 0.112mmol), followed a few minutes
later by sodium borohydride (0.009g, 0.224mmol). Stir-
ring continued for 30min, after which time 5% aqueous
hydrochloric acid (2mL) was added to the mixture, and
the mixture was poured onto DCM (10mL) and ex-
tracted. The organic layer was washed with water
(10mL), dried and concentrated in vacuo to yield the
crude product as a colourless oil. Chromatography
(1:1 ethyl acetate–hexane; Rf = 0.48) yielded 19
(C17H18NO6Cl3) as a white solid, recrystallised from
1
ethyl acetate (0.048g, 98% yield). Mp: 131–132ꢂC. H
NMR (d): 1.65–1.85 (3H, m, H7a, H2e, H4e); 1.93–
2.39 (3H, m, H2a, H4a, H7e); 3.90 (0.75H, dddd, H3,
J3a,2e = 6.3, J3a,2a = 9.6, J3a,4e = 6.3, J3a,4a = 9.6); 4.04
(0.25H, t, H3, J3e,2a = 5.4, J3e,4a = 5.4); 4.69 (1H, dd,
H1, J = 6.0, 11.7); 4.80–4.96 (3H, m, OH, CH2CCl3);
5.05 (1H, dd, H5, J = 3.3, 6.3); 5.97 (2H, s, OCH2O);
6.15 (0.75H, dd, OH, J = 2.4, 8.7); 6.41 (0.25H, dd,
OH, J = 2.7, 8.7); 6.76–6.96 (3H, m, ArH · 3). 13C
NMR (d): 33.9, 34.1, 34.6, 34.9 (CH2 · 3, C4, C2, C7);
58.2(58.3*) (CH, C1); 64.8 (CH, C3); 65.4 (CH, C5);
74.6 (OCH2CCl3); 95.6 (CCl3); 101.3 (101.3*) (OCH2O);
105.7 (ArCH); 108.4 (108.6*) (ArCH); 119.7 (119.8*),
121.3 (121.5*) (ArCH); 124.6 (C6), 126.0 (126.1*) (ispo
C); 142.0 (142.1*) (ispo C); 147.8 (148.1*) (ipso C);
+
149.9 (NC@O). MS (CI+): m/z 438, 440, 442(MH
,
438, 5%); 420, 422, 424 (MH+ ꢀ H2O, 420, 100%);
402, 404, 406 (402, 13%); 386, 388, 390 (386, 25%).
HRMS (CI+): Found: 421.0040; Required: 421.0065
for C17H16NO535Cl237Cl (loss of H2O).
4.2.14. 8-(2,2,2-Trichloroethylformate)-6b-phenyl-8-aza-
bicyclo[3.2.1]octane-3b,6a-diol (18). To a stirred solution
of 0.4M cerium chloride heptahydrate in methanol
(5mL) under nitrogen was added the mixture of 14
and 26 (0.120g, 0.306mmol), followed a fewmin later
by sodium borohydride (0.021g, 0.547mmol). Stirring
continued for 4 h, after which time 5% aqueous hydro-
chloric acid was added to the mixture, and then the mix-
ture poured onto DCM (10mL) and extracted. The
organic layer was washed with water (10mL), dried
and concentrated in vacuo to yield a colourless oil which
crystallised upon standing to a white solid. Mp: 131–
132ꢂC. Chromatography (1:2ethyl acetate–hexane)
yielded unreacted 14 (0.072g, 60% recovery) and 18
(C16H18NO4Cl3) as a colourless oil (Rf 0.43, 1:2ethyl
acetate–hexane, 0.049g, 100% yield based on recovered
4.2.16. General procedure for the removal of the 2,2,2-
trichloroethylformate protecting group to yield secondary
amine derivatives. The 2,2,2-trichloroethoxycarbonyl
derivative (0.10–1.50mmol) and zinc dust (10equiv)
were stirred in 90% acetic acid (2–20mL) at 40ꢂC for
2days. The reaction mixture was basified (ammonia,
pH9) and extracted with diethyl ether (3 · 100mL).
The combined organic extracts were washed with so-
dium chloride (satd) (100mL), water (2 · 100mL), dried
and concentrated in vacuo to give the desired secondary
amine derivatives. In this way derivatives 2, 4, 6, 10, 12,
34, 35, 36 and 37 were prepared. Hydrochloride salts of
these bases were prepared by dissolving the aryl tropa-
nol derivatives (0.10–1.00mmol) in diethyl ether (1–
2mL), and treating the solution dropwise with 1M
hydrochloric acid in diethyl ether (0.50–1.00mL). The
precipitate was filtered and dried under high vacuum
to yield the desired hydrochloride salt.
1
14). H NMR (d): 1.87 (1H, m, H7a); 2.16–2.38 (3H,
m, H2e, H4e, H7e); 2.48 (1H, dd, H2a, J2a,2e = 8.7);
2.68–2.78 (1H, m, H4a); 3.70 (1H, 2 · br s, OH); 4.24–
4.27 (2H, m, H1, H3); 4.39–4.47 (1H, m, H5); 4.68–
4.89 (2H, m, CH2CCl3); 5.55 (1H, br d, OH, J = 12.3);

S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
5649
4.2.16.1. 6b-Phenyl-8-azabicyclo[3.2.1]octan-3-spiro-
20-(10,30-dioxolane)-6-ol (12). Reaction of 10 (0.075g,
0.17mmol) yielded 12 (C15H19NO3) after chromatogra-
phy (ethyl acetate) as a colourless oil (0.025g, 51%
(1H, m, ArH); 6.88–6.95 (2H, m, ArH · 2). 13C NMR
(d): 37.9 (CH · 2, C4), 41.4 (CH · 2, C2); 48.0
(CH · 2, C7); 49.7 (OCH · 3); 56.2(CH, C1); 67.1
(CH, C5); 88.6 (C6); 100.9 (OCH2O); 105.8, 106.2
(ArCH · 2); 107.9 (C3); 117.8 (ArCH); 136.0, 146.4,
147.5 (ipso C · 3). MS (CI+): m/z 276 (MH+, 70%);
244 (MH+ ꢀ MeOH, 65%); 154 (55%). HRMS (CI+):
Found: 276.1240; Required: 276.136 for C15H18NO4.
1
yield). H NMR (d): 1.78 (2H, br s, OH, NH); 1.93
(2H, dd, H2e, H4e, J = 4.2, 15.0); 2.05 (1H, d, H7a,
J = 7.2); 2.27 (1H, d, H2a(H4a), J = 14.4); 2.45(1H, d,
H4a(H2a), J = 14.4); 2.62 (1H, dd, H7e, J = 7.8, 8.1);
3.38 (1H, s, H1); 3.71 (1H, t, H5 J = 3.9, 7.8); 3.92–
3.99 (2H, m, OCH2); 4.03–4.14 (2H, m, OCH2); 7.20–
7.26 (1H, m, ArH); 7.33 (2H, dd, ArH · 2, J = 7.2,
8.1); 7.67 (2H, dd, ArH · 2, J = 1.2, 8.4). 13C NMR
(d): 39.5 (CH2, C7); 43.4 (CH2, C4); 44.9 (CH2, C2 );
53.5 (CH · 2, C1, C5); 63.6 (OCH2); 64.4 (OCH2);
82.2 (C6); 107.5 (C3); 124.7, 126.4, 127.9 (ArCH · 5);
148.9 (ipso-C). MS (CI+): m/z 262 (MH+); 244
(MH+ ꢀ H2O); 184.
4.2.16.5. 6ab-Phenyl-2,5-methano-hexahydro-2H-furo-
[3,2-b]pyrrol-6aa,2b-diol (28). Reaction of 26 (0.090g,
0.229mmol) yielded hemi-ketal 28 (C13H15NO2) after
chromatography (10:2ethyl acetate–methanol; Rf 0.12)
1
as a colourless oil (0.015g, 30% yield). H NMR (d):
1.88 (1H, d, H7a, J = 12.3); 1.89–2.20 (4H, m, H2e,
H4e, H2a, H4a); 2.24 (1H, d, J = 11.7, H7e); 2.99
(2H, br s, N H, OH); 3.81 (1H, s, H1); 3.89 (1H, s,
H5); 7.23–7.44 (5H, m, ArH · 5). 13C NMR (d): 39.5
(CH2, C4), 46.1 (CH2, C2); 47.7 (CH2, C7); 56.1 (CH,
C1); 67.3 (CH, C5); 89.3 (C6); 103.5 (C3); 124.8,
126.8, 127.1, 127.9, 128.2 (ArCH · 5); 141.6 (ipso C).
MS (CI+): m/z 218 (MH+); 200 (MH+ ꢀ H2O). HRMS
(CI+): Found: 218.1175; Required: 218.1181 for
C13H16NO2.
4.2.16.2. 6b-(3,4-Methylenedioxy)-8-azabicyclo[3.2.1]-
octan-3-spiro-20-(10,30-dioxolane)-6-ol (13). Reaction of
11 (0.09g, 0.19mmol) yielded 13 (C16H19NO5) after
chromatography (ethyl acetate) as
a white solid
(0.021g, 37% yield). Mp: 218–220ꢂC. 1H NMR (d):
1.74 (2H, br s, OH, NH); 1.91 (2H, dd, H2e, H4e,
J = 4.2, 14.7); 2.03 (1H, d, H7a, J = 6.6); 2.24 (1H, d,
H2a(H4a), J = 14.4); 2.41 (1H, d, H4a(H2a), J = 14.4);
2.55 (1H, dd, H7e, J = 8.1, 14.1); 3.38 (1H, d, H1,
J = 4.2); 3.69 (1H, dd, H5, J = 4.2, 8.1); 3.94–3.99 (2H,
m, OCH2); 4.02–4.16 (2H, m, OCH2); 5.92(H2 , s,
OCH2O) 6.75 (1H, d, ArH5, J = 8.1); 7.10 (1H, dd,
ArH6, J = 1.8, 8.1); 7.27 (1H, d, ArH2, J = 2.1). 13C
4.2.16.6. 6ab-(3,4-Methylenedioxyphenyl)-2,5-meth-
ano-hexahydro-2H-furo[3,2-b]pyrrol-6aa,2b-diol
(29).
Reaction of 27 (0.040g, 0.092mmol) yielded 29
(C14H15NO4) after chromatography (10:2ethyl ace-
tate–methanol; Rf 0.13) as a colourless oil (0.014g,
58% yield). 1H NMR (d):1.84 (1H, dd, H7a, J7a,7
e = 12.0,J7a,1 = 3.3); 1.95–2.03 (4H, m, H2e, H4e, H2a,
H4a); 2.18 (1H, d, J7a,7e = 11.7, H7e); 3.07 (2H, br s,
NH, OH); 3.75 (1H, s, H1); 3.86 (1H, s, H5); 5.93
(2H, s, OCH2O); 6.76 (1H, d, J = 8.1, ArH); 6.66 (1H,
d, J = 1.5, ArH); 6.90 (1H, dd, J = 8.1, 1.5 ArH). 13C
NMR (d): 39.3 (CH2, C4), 46.1 (CH2, C2); 47.3 (CH2,
C7); 55.9 (CH, C1); 67.1 (CH, C5); 89.3 (C6); 101.0
(OCH2O); 103.5 (C3); 106.0 (ArCH); 107.9 (ArCH);
118.1 (ArCH); 135.7.0, 146.7, 147.8 (ipso C · 3). MS
(CI+): m/z 262 (MH+, 40%); 244 (MH+ ꢀ H2O, 80%).
HRMS (CI+): Found: 261.1002; Required: 261.1001
for C14H15NO4.
NMR (d): 37.4 (CH2, C7); 40.8 (CH2, C4); 44.2(CH ,
2
C2); 56.2 (CH · 2, C1, C5); 61.3 (OCH2); 67.3
(OCH2); 66.5 (C6); 101.2(OCH 2O); 105.7, 106.2
(ArCH · 2); 107.6 (C3); 118.1 (ArCH); 135.8, 147.0,
147.9 (ipso-C · 3). MS (CI+): m/z 306 (MH+); 288
(MH+ ꢀ H2O); 244, 184. HRMS (CI+): Found:
305.1254; Required: 305.1263 for C16H18NO5.
4.2.16.3.
2-Methoxy-6ab-phenyl-2,5-methano-hexa-
hydro-2H-furo[3,2-b]pyrrol-6a-ol (30). Reaction of 22
(0.05g, 0.114mmol) yielded 30 (C14H17NO2) after chro-
matography (ethyl acetate) as a pale yellow oil (0.022g,
1
85% yield). H NMR (d): 1.78 (1H, d, H7a, J = 10.5);
1.92–2.04 (3H, m, H2e, H4e, H7e); 2.23–2.29 (2H, m,
H2a, H4a); 2.50 (1H, br s, NH); 3.49 (3H, s, OCH3);
3.79 (1H, d, H1, J = 5.1); 3.88 (1H, d, H5, J = 2.7);
7.24–7.46 (5H, m, ArH · 5). 13C NMR (d): 38.1 (CH2,
C4), 41.4 (CH2, C2); 48.5 (CH2, C7); 49.7 (OCH3);
56.4 (CH, C1); 67.3 (CH, C5); 88.7 (C6); 106.2(C3);
124.6, 126.9, 128.1, 128.3 (ArC · 5); 142.0 (ipso C).
MS (CI+): m/z 232 (MH+, 100%); 200 (MH+ ꢀ MeOH,
40%). HRMS (CI+): Found: 231.1266; Required:
231.1260 for C14H17NO2.
4.2.16.7. 6b-Phenyl-8-azabicyclo[3.2.1]octane-3a,6b-
diol (1). Reaction of 18 (0.059g, 0.149mmol) yielded 1
(C13H17NO2) after chromatography (10:2ethyl ace-
tate–methanol, Rf 0.18) as a colourless oil, which was
crystallised from DCM (0.012g, 36% yield). 1H NMR
(d): 1.89 (1H, dd, H7a, J = 11.1, 14.7); 2.03 (1H,
2 · dd, H4e, J = 4.5, 4.8); 2.13 (1H, 2 · dd, H2e,
J = 4.5, 4.8); 2.36 (2H, dd, H2a, H4a, J = 14.4, 15.6);
2.64 (1H, dd, H7e, J = 7.5, 14.4); 3.29 (1H, s, OH);
3.53–3.56 (4H, m, H1, H5, NH, OH); 4.17 (1H, dd,
H3a, J = 5.1, 10.2); 7.25 (1H, d, ArH, J = 7.2); 7.34
(2H, dd, ArH · 2, J = 7.2, 7.8); 7.60 (2H, dd,
ArH · 2, J = 7.2, 1.2). 13C NMR (d): 33.5 (CH2, C4),
40.6 (CH2, C2); 45.5 (CH2, C7); 53.0 (CH, C1); 63.7
(CH, C3); 64.1 (CH, C5); 82.8 (C6); 124.7, 126.7,
128.3 (ArCH · 5); 148.7 (ipso C). MS (CI+): m/z 220
(MH+, 40%); 202 (MH+ ꢀ H2O, 100%). HRMS (CI+):
Found: 220.1335; Required: 220.1338 for C13H18NO2.
4.2.16.4. 2-Methoxy-6ab-(3,4-methylenedioxyphenyl)-
2,5-methano-hexahydro-2H-furo[3,2-b]pyrrol-6a-ol (31).
Reaction of 23 (0.058g, 0.120mmol) yielded 31
(C15H17NO4) as a pale yellow oil (0.025g, 78% yield).
1H NMR (d): 1.91–2.01 (3H, m, H2e, H4e, H7a);
2.11–2.28 (3H, m, H2a, H4a, H7e); 2.62 (1H, br s,
NH); 3.48 (3H, s, OCH3); 3.74 (1H, br d, H1, J = 3.6);
3.87 (1H, br s, H5); 5.95 (2H, s, OCH2O); 6.77–6.80

5650
S. J. McGinty et al. / Bioorg. Med. Chem. 12 (2004) 5639–5650
14, 107–113; (b) Chalothorn, D.; McCune, D. F.; Edel-
4.2.16.8. 6b-(3,4-Methlenedioxyphenyl)-8-azabicyclo-
mann, S. E.; Tobita, K.; Keller, B. B.; Lasley, T. D.; Perez,
D. M.; Tanoue, A.; Tsujimoto, G.; Post, G. R.; Piascik,
M. T. J. Pharmacol. Exp. Ther. 2003, 305, 1045–1053; (c)
Graham, R. M.; Perez, D. M.; Hwa, J.; Piascik, M. T.
Circ. Res. 1996, 78, 737–749.
[3.2.1]octane-3a,6b-diol (3). Reaction of 19 (0.048g,
0.109mmol) yielded 3 (C14H17NO2) after chromatogra-
phy (10:2ethyl acetate–methanol; Rf 0.12) as a colour-
less oil which was crystallised from diethyl ether
1
(0.015g, 52% yield). H NMR (d): 1.90 (1H, dd, H7a,
4. (a) Alexander, S. P. M.; Mathie, A.; Peters, J. A. Br. J.
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We wish to thank the NH&MRC for financial support,
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmc.2004.07.063.
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