Synthesis of 5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-azabicyclo[3.2. 1]octane derivatives as constrained aryl-piperidines with activity as triple re-uptake inhibitors

Article abstract of DOI:10.1016/j.tetlet.2010.07.145

Stereochemical and synthetic aspects encountered during the preparation of the four possible isomers of 1 are reported. The 5-aryl 2-azabicyclo [3.2.1] octane derivatives represent a novel class of compounds which can be deemed as an example of aryl-piperidine conformationally constrained of potential interest for medicinal chemistry exploration. In particular isomers of 1 are characterised by a potent in vitro serotonine, dopamine and noradrenaline re-uptake inhibitor (TRUI) activity superior/comparable to standard compounds such as DOV 21,947 and DOV 102,677.

Full text of DOI:10.1016/j.tetlet.2010.07.145

Tetrahedron Letters 51 (2010) 5521–5524
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-azabicyclo
[3.2.1]octane derivatives as constrained aryl-piperidines with activity as
triple re-uptake inhibitors
⇑
⇑
Roberto Profeta , Jens Klein, Simone Spada, Francesco Ferroni, Alfredo Paio, Daniele Andreotti
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereochemical and synthetic aspects encountered during the preparation of the four possible isomers of
1 are reported. The 5-aryl 2-azabicyclo [3.2.1] octane derivatives represent a novel class of compounds
which can be deemed as an example of aryl-piperidine conformationally constrained of potential interest
for medicinal chemistry exploration. In particular isomers of 1 are characterised by a potent in vitro
serotonine, dopamine and noradrenaline re-uptake inhibitor (TRUI) activity superior/comparable to stan-
dard compounds such as DOV 21,947 and DOV 102,677.
Received 16 June 2010
Revised 22 July 2010
Accepted 26 July 2010
Available online 3 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Exploration of aryl-piperidine motifs by several pharmaceutical
industries has resulted in the identification of interesting biologi-
cally active molecules particularly for application in the CNS area.
In fact, these compounds have been widely investigated as NMDA
receptor antagonists, serotonin re-uptake inhibitors (SSRI), dual or
triple re-uptake inhibitors (TRUI—inhibitors of the re-uptake of
three important neurotransmitters namely 5-HT [serotonin], DA
[dopamine] and NE [noradrenaline]) and other mechanisms for
indications such as unipolar depression, Alzheimer’s and Parkin-
son’s diseases.1 The constraint of the piperidine ring represents
an efficient expedient to achieve biological potency and selectivity
within a receptor family.
further example of a constrained 4-aryl-piperidine, see compound
2 in Figure 1. Single enantiomers have been characterised both
in vitro and in vivo as a CNS penetrant TRUI with potential appli-
cation for unipolar depression.
During our research activity we were interested in preparing a
novel class of compounds such as TRUIs and we envisaged the pos-
sibility to achieve this with a new class of constrained 4-aryl-
piperidines,7 with a more rigid C2 carbon linkage and that was
amenable to further chemical manipulations. A schematic example
is reported in Figure 2. In particular, to evaluate whether this class
of compounds can deliver a triple re-uptake inhibitor, compound 1
was designed. We choose the 5-aryl 2-azabicyclo [3.2.1] octane
lactam 3, as a key intermediate (Scheme 1). It contains multiple
functional groups that can allow versatile manipulations and dec-
orations. It represents an ideal starting point for a SAR exploration
around this template. The 5-aryl 2-azabicyclo [3.2.1] octane tem-
plate is a very rigid structure and the substituents are locked in
their positions as depicted in Figure 3.
It is clear that among the three chiral centres present in com-
pound 3, two of them are mutually related by the C2 carbon atoms
sequence bridging the 1 and 5 positions of the piperidine ring.
The 5-aryl substituent assumes an equatorial position whilst
the substituent at 4 position could either be in an equatorial (anti
diastereoisomer) or an axial position (syn diastereoisomer).
Clearly, the biological response to this variation and to the abso-
lute stereochemistry will be diverse and important to investigate.
Therefore, in the first instance all possible isomers of 1 were of po-
tential interest.
A few examples of constrained aryl-piperidines that are CNS ac-
tive are listed in Figure 1: tropane derivatives and benzomorfane
scaffolds are classical examples2 of constrained aryl-piperidines.
In these cases the piperidine ring has been constrained, respec-
tively, by a C2 and C3 carbon linkage between 1 and 5 positions
or as in the case of DOV 21,947 and DOV 102,67 where positions
1 and 5 are directly linked to give a [3.1.0] bicyclic motif.3 Likewise
for cocaine analogues, often the 2 position is a point of further
diversification of the molecule that enables the modulation of its
physico-chemical and biological properties. The anti-depressant
paroxetine, which bears both substituents in the equatorial posi-
tions, can also be considered as a 4-aryl-piperidine with a re-
stricted conformation.4 Also the well-known Parkinson’s disease
animal model inducer MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine), that is, characterised by the presence of a double
bond can be considered as an example of an aryl-piperidine with
a reduced degree of freedom.5 Recently GSK has published6
a
The malonamide motif present in 3 is a key strategic feature for
preparation of 1 and the ester moiety can allow a relatively easy
functionalisation at the 4 position. Synthesis of intermediate 3 is
reported in Scheme 1.
⇑
Corresponding authors. Tel.: +39 0458219953; fax: +39 0458218196 (D.A.).
E-mail address: daniele.andreotti@aptuit.com (D. Andreotti).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.145

5522
R. Profeta et al. / Tetrahedron Letters 51 (2010) 5521–5524
F
TROPANE
O
O
CO2CH3
N
CO2CH3
1
N
1
R
5
O
5
O
3
3
N
O
COCAINE ANALOGUES
COCAINE
PAROXETINE
Cl
Cl
Cl
Cl
5
1
OH
N
O
1
5
N
N
N
DOV21,947, 1R,5S (+)
DOV102,67, 1S,5R (-)
MPTP
BENZOMORFANE
2
Figure 1. Constrained piperidine examples active in CNS.
R
2
H
Aryl and heteroaryl
exploration
1
N
X
N
X
Cl
Cl
5
R 4
3
H
C2 linkage
(1,5-position)
Ar
ANTI
SYN
R
O
1 X = H2, R=CH2OCH3
3 X = O, R=COOEt
R'
N
N
H
Figure 3. Relative stereochemistry of the two possible diastereoisomers.
Functional Groups
Introduction
1
Basicity
modulation
(4-stereoisomers)
Figure 2. 5-Aryl 2-azabicyclo [3.2.1] octane as new triple re-uptake inhibitor.
2
O
N
N
O
1
H4
3b
SYN
H8
3a
ANTI
H4
5
The first problem to address was the preparation of the inter-
mediate b-amino ketone 5.
CO2Et
CO2Et
H6
Despite the fact that several 1,4-Michael additions of benzyl
Cl
and dibenzyl amines catalysed by Lewis acids on a,b-unsaturated
Cl
Cl
Cl
ketones are reported in the literature,8 in our hands, only traces
of target product were detected applying these procedures onto
Figure 4. Homonuclear dipolar interactions (1H–1H-ROE) exploited to assign the
relative anti and syn stereochemistry of 3a and 3b.
Cl
EtO2C
CO2Et
O
Cl
O
CO2Et
CO2Et
a
c
b
Boc
N
Boc
N
H
H
N
Boc
H
7
4
5
6
50/50 =Trans/Cis
N
O
N
O
N
O
CO2Et
CO2Et
d
CO2Et
e
Cl
Cl
Cl
Cl
Cl
(Anti)
(Syn)
3b
3a
Cl
5/95=Anti/Syn
3
Scheme 1. Reagent and conditions: (a) (1) TMSN3, CH3COOH, Et3N, DCM, rt; (2) H2, Pd/C, EtOAc; (3) Boc2O, 30%; (b) diethylmalonate, TiCl4, CCl4/THF, 58%; (c) 3,4-
dichlorophenyl magnesium bromide, CuI, THF, rt; (d) (1) TFA, DCM; (2) Et3N, DCM, 120 °C MW, 40 min, 43% after three steps; (e) prep HPLC separation.

R. Profeta et al. / Tetrahedron Letters 51 (2010) 5521–5524
5523
cyclopentenone 4. This finding prompted us to consider a more
conservative two-step sequence involving a 1,4-Michael addition
of azide followed by reduction and in situ protection to give a sta-
ble N-Boc cyclopentanone9 5 in an overall 30% yield. Due to the
presence of the acid-labile protective group N-Boc on intermediate
TiCl4 as the activator in THF/CCl4 solution at 0 °C followed by pyr-
idine treatment to complete the formation of the
a,b-unsaturated
system.
Intermediate 6 was then reacted via 1,4-Michael addition with
an excess of 3,4-dichloro phenylmagnesium bromide due to the
presence of the acidic NH-Boc moiety using CuI as the catalyst.
The aryl group was expected to mainly enter from the less hin-
dered face of 6, however, the coordination of the Grignard with
the NH-Boc might have counterbalanced the expected favourable
steric effect giving rise to 7 as a ꢀ1:1 ratio of trans:cis isomers.
Separation of the two isomers 7 was achieved in the next steps;
cleavage of the N-Boc-protecting group using TFA followed by ba-
sic treatment to obtain the corresponding free amine, which in
turn was cyclised to lactam 3.
5, the a,b-unsaturated malonic system 6 was obtained by applying
a mild version of the Knoevenagel condensation reaction, using
Less hindered face
F
F
F
O
O
H
Of course, only the isomer with the right geometry underwent
intramolecular cyclisation affording the corresponding lactam 3.
The polar nature of the unreacted isomer facilitated the isolation
of the desired product 3 which was obtained as a mixture of two
isomers 3a and 3b (anti/syn = 5/95). Relative stereochemistry of
3a and 3b was assessed by homonuclear dipolar interactions
(1H–1H-ROE), Figure 4.
EtO
H
H
O
N
b
N
O
a
Ar
EtO
N
Ar
Ar
EtO
Li+
O
O
O
O
3b
3a
Anti
Li+
Syn
Only the major diastereoisomer 3b (syn) showed a strong H4–
H6 ROE supporting the view that these two hydrogens are on the
Scheme 2. Stereochemical inversion of 3b to 3a. Reagents and conditions: (a)
LiHMDS, À78 °C, THF; (b) TFA, from À78 °C to rt, 90%.
O
O
H
H
N
N
O
N
O
COOEt
a
OH
b
Cl
Cl
Cl
Cl
Cl
Cl
8a
9a
c
3a Anti
H
H
N
N
O
O
Cl
Cl
Cl
Cl
1a(e1)
1a (e2)
O
O
H
H
N
N
O
N
O
a
CO2Et
b
OH
Cl
Cl
Cl
Cl
Cl
Cl
Syn
3b
8b
9b
c
H
H
N
N
O
O
Cl
Cl
Cl
Cl
1b(e1)
1b(e2)
*
Scheme 3. Reagents and conditions: (a) (1) BH3 THF, reflux then MeOH/HCl; (2) NaOH, THF, Boc2O; (b) (1) NaH, MeI, THF; (2) TFA, DCM, 30% over five steps; (c) Chiral Prep
HPLC. 1a(e1), 1a(e2), 1b(e1) and 1b(e2) are single enantiomers and their relative stereochemistry is shown. Absolute stereochemistry has not been determined.

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R. Profeta et al. / Tetrahedron Letters 51 (2010) 5521–5524
Table 1
enantiomers 1a(e1), 1a(e2), 1b(e1) and 1b(e2) as shown in
Scheme 3. All of these were tested as TRUIs in comparison with
two standard compounds DOV 21,947 and DOV 102,677. All four
compounds showed excellent in vitro potency in blocking the
binding of the three human transporters DAT, SERT and NET.13
Additionally, the relative potency ratio for the three neurotrans-
mitter transporters is more balanced in the case of the syn isomers
1b(e1) and 1b(e2) rather than in the case of the anti isomers 1a(e1)
and 1a(e2) see Table 1. In conclusion, the synthesis of a new con-
formationally constrained 4-aryl-piperidine class such as 1 has
been achieved. Both isomers 9b and 9a have been isolated using
a suitable chemical strategy that has allowed to epimerise the
syn isomer 3b to the anti 3a isomer. Final compounds 1a(e1),
1a(e2), 1b(e1) and 1b(e2) were isolated as single enantiomers
and showed to be potent in vitro TRUIs with different potency ra-
tios for the three transporters, SERT, DAT and NET.
Binding values at three transporters (DAT, SERT, NET) expressed as pKi
Compounds
hDAT pKi
hSERT pKi
hNET pKi
DOV 21,947
DOV 102,677
9b
1b(e1)
1b(e2)
9a
7.10
7.42
8.50
8.68
8.00
8.80
8.90
7.50
6.85
7.09
8.50
8.85
8.50
10.00
10.10
8.20
6.83
7.23
8.10
8.24
8.30
8.80
8.82
7.10
1a(e1)
1a(e2)
SEM for hDAT/hSERT/hNET data sets is 0.1.
same side of the molecule, while isomer 3a (anti) showed a signif-
icant correlation between H4 and H8 permitting to assign the anti-
relationship to this isomer as depicted in Figure 4. It was surprising
to us to find out that isomer 3b bearing the ethyl ester in a pseudo-
axial position was the major one. Likely, the experimental condi-
tion used to obtain lactam 3 reflects the relative thermodynamic
stability of the two diastereoisomers, see Figure 3. Although,
molecular mechanic and quantum mechanic calculations10 are in
agreement with the result obtained predicting the syn isomer as
the favourable form, these studies cannot explain the high degree
of stereoselectivity observed (anti/syn = 5/95).
Acknowledgements
We thank all the colleagues who helped in generating the data
reported in this manuscript, Dr. Michele Dal Cin and Dr. Sylvie
Gehanne for HPLC purifications, Dr. Beatrice Oliosi for biological
data and Dr. Alfonso Pozzan for quantomechanic calculations. We
thank Dr. Fabrizio Micheli, Dr. Daniele Donati and Dr. Romano Di
Fabio for their support during the progression of this activity.
Separation of these two isomers has proven difficult; from a
practical point of view only isomer 3b was recovered as a pure
material by flash chromatography whilst a pure sample of the iso-
mer 3a was obtained by preparative HPLC separation.
References and notes
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Reduction of isomer 3b to the corresponding 8b was achieved
using borane in THF at reflux followed by in situ protection of
the secondary nitrogen by reaction with (Boc)2O under Schotten–
Baumann conditions.11 With the aim of converting the syn isomer
3b to the corresponding anti-form, 3a, we started to investigate
different conditions for inverting the stereochemistry of the ethyl
ester. Among them, we found that treatment of 3b with lithium
hexamethyldisilazane (2 equiv) as a base in THF at À78 °C followed
by addition of TFA was particularly successful, Scheme 2. We as-
sumed that the proton would have entered from the less hindered
face of the molecule, opposite to the C2 carbon bridge, to give the
anti isomer 3a. We were pleased to see that our assumption was
fully supported by the experimental results and complete epimer-
isation from 3b to 3a was obtained. However, as expected the iso-
lated pure 3a anti isomer proved to have limited stability and after
36–48 h at room temperature we observed re-conversion to the 3b
syn isomer.
Nevertheless, this finding did not limit the possibility of obtain-
ing the desired amino-alcohol 8a, which retained the relative ste-
reochemistry, through reduction of a freshly prepared sample of
3a. Separately, both compounds 8a and 8b were methylated using
the same reaction conditions, NaH and MeI in THF. Then removal of
the N-Boc-protecting groups, using TFA, gave 9a and 9b, both in
30% overall yield. Eventually, racemic 9a and 9b were resolved
by chiral preparative HPLC12 to obtain the corresponding single
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10. Initial global minimum-energy structures for 3a and 3b were generated using
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field. Effective energies are: 3a (6.42 kcal/mol) versus 3b (5.84 kcal/mol).
11. (a) Schotten, C. Chem. Ber. 1884, 21, 2544–2547; (b) Baumann, E. A. Chem. Ber.
1886, 19, 3218–3222.
12. Preparative Chiral HPLC System conditions to resolve 9a; Supercritical Fluid
Chromatography; Chiral Pack AD-H(25 Â 0.46 cm); Ethanol + 0.1IPA; t = 35 °C,
P = 100 bar; flow = 2 ml/min to obtain 1a(e1) (tR = 7.92 min) and 1a(e2)
(tR = 12.5 min). System conditions to resolve 9b: Chiralcel OD-H, n-hexane/
isopropanol + 0.1% isopropylamine 90/10, flow: 14 ml/min to obtain
enantiomers, to obtain 1b(e1) (tR = 8.983 min) and 1b(e2) (tR = 11.112 min).
13. Micheli, F.; Cavanni, P.; Arban, R.; Benedetti, R.; Bertani, B.; Bettati, M.;
Bettelini, L.; Bonanomi, G.; Braggio, S.; Checchia, A.; Davalli, S.; Di Fabio, R.;
Fazzolari, E.; Fontana, S.; Marchioro, C.; Minick, D.; Negri, M.; Oliosi, B.; Read, K.
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