Amine-mediated tandem conjugative isomerization-bridging Michael addition: Concise synthesis of 1-azabicyclo[3.3.1]nonanes

Article abstract of DOI:10.1016/j.tetlet.2012.04.069

To reach densely functionalized 1-azabicyclo[3.3.1]nonane frameworks synthesis, a stereocontrolled bridging Michael addition involving an unexplored C-5/C-6 disconnection strategy was studied. 1-Azabicyclo[3.3.1]nonane scaffolds have been diastereoselectively elaborated in fairly good yields by two concise pathways implying pyrrolidine derivative organocatalyst or enantiopure 1-phenylethylamine.

Full text of DOI:10.1016/j.tetlet.2012.04.069

Tetrahedron Letters 53 (2012) 3296–3300
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Tetrahedron Letters
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Amine-mediated tandem conjugative isomerization-bridging Michael addition:
concise synthesis of 1-azabicyclo[3.3.1]nonanes
⇑
⇑
Anh Ngoc Ngo, Khadija El Kassimi, Zacharias Amara, Emmanuelle Drège , Delphine Joseph
Univ. Paris-Sud, Equipe de Chimie des Substances Naturelles, UMR CNRS 8076 BioCIS, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry, France
a r t i c l e i n f o
a b s t r a c t
Article history:
To reach densely functionalized 1-azabicyclo[3.3.1]nonane frameworks synthesis, a stereocontrolled
bridging Michael addition involving an unexplored C-5/C-6 disconnection strategy was studied. 1-Azabi-
cyclo[3.3.1]nonane scaffolds have been diastereoselectively elaborated in fairly good yields by two con-
cise pathways implying pyrrolidine derivative organocatalyst or enantiopure 1-phenylethylamine.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 March 2012
Revised 12 April 2012
Accepted 16 April 2012
Available online 23 April 2012
Keywords:
Michael reaction
Cyclization
Organocatalysis
Chiral auxiliaries
Cinchona alkaloids represent the most famous example of poly-
functionalized 1-azabicyclic frames that are widely found in
unnatural as well as natural biologically active compounds.1–3 Dur-
ing the past decade, 1-azabicycloalkanes (so-called ‘cage amines’)
have mobilized considerable attention of medicinal chemists nota-
bly in the design and synthesis of neuronal nicotinic acetylcholine
receptor (nAChR) subtype-selective ligands.3 In the context of
developing new treatments of psychotic and neurodegenerative
disorders including nicotine addiction, autism, schizophrenia and
Parkinson and Alzheimer diseases, hetero-aromatic substituted 1-
azabicyclo[3.3.1]nonanes have been recently prepared as nAChR-
Sequential Dieckmann
Intramolecular SN2
under solid phase
transfer catalysis5
cyclization/
3
6-10
4
decarboxylation
EtOC
R
EtO2C
N
H2N
Br
N
1
2
9
3,4-Disconnection
1,2-Disconnection
Br
Scheme 1. Two main strategies for azabicyclo[3.3.1]nonane scaffold synthesis.
OH
N
O
6
CO2R1
CO2R2
CO2R1
Cl
Bridging Michael
CO2R2
CO2R1
annulation
O
a
7 subtype-selective ligands.4,5 Therefore, intense efforts have
N5
N
H
been engaged in developing general synthetic routes to aza-
5,6-Disconnection
bridged azabicyclic skeletons.3
1-azabicyclo[3.3.1]
3
2
nonan-4-one 1
In contrast to more constrained 1-azabicycloalkanes such as
quinuclidine, the higher [3.3.1] homologues have been much less
studied. A literature review underlines the lack of common methods
for their synthesis and, to our knowledge, only two strategies have
been exemplified until now (Scheme 1). Kohn and co-workers de-
scribed the preparation of parent 8-substituted aza-bridged
[3.3.1]bicyclic amines using a Dieckmann cyclization as the key
step.6 This Dieckmann route was firstly reported in 1952 by Stern-
bach and Kaisern.7 Later, Martell,8 Halpern,9 King10 and Feuerbach4b
related the preparation of 1-azabicyclo[3.3.1]nonan-3-one deriva-
tives according to the same strategy. More recently, Slowinski
proposed an alternative multi-step sequence for the synthesis of
bridgehead-substituted 1-azabicylo[3.3.1]nonanes: the azabicyclic
Scheme 2. 1-Azabicyclo[3.3.1]nonanone retrosynthesis through unexplored C(5)/
C(6)-disconnection.
skeleton was built at the late stages by an intramolecular nucleo-
philic substitution using solid phase-transfer catalysis.5b,c
These two main strategies gave monosubstituted 1-azabicyclo-
[3.3.1]nonanes without stereoselectivities.
Our group has earlier described the stereocontrolled synthesis
of quinuclidine nucleus through asymmetric bridging annulation
of chiral b-enamino ester derived from (S)-phenylethylamine.11
In addition, whilst a resurgence of interest in organocatalysed Mi-
chael reaction, the synthesis of highly functionalized 1-azabicy-
clo[3.3.1]nonan-3-ones
Michael addition involving a C(5)/C(6)-disconnection remains still
1 through a stereoselective bridging
⇑
Corresponding authors. Tel.: +33 1 46 83 57 30; fax: +33 1 46 83 57 52 (D.J.).
E-mail address: delphine.joseph@u-psud.fr (D. Joseph).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.069

A. N. Ngo et al. / Tetrahedron Letters 53 (2012) 3296–3300
3297
unexplored (Scheme 2). Indeed, over the last decade, a consistent
CO2R
OH
N
cross-
theme among the catalytic amine-mediated conjugate addition
was concentrated to the development of its intermolecular ver-
sion.12 To the best of our knowledge, the intramolecular process
has received much less attention and the main investigations in
this area were reported for the 1,4-addition of enols derived from
aldehydes as reactive nucleophiles to potent electrophilic Michael
acceptors such as enals, enones, vinylsulfones or alkylidene
malonates.13
In this context, we envisaged to expand the scope of amine-
mediated intramolecular Michael addition by studying the chal-
lenging construction of 1-azabicyclo[3.3.1]nonane frameworks
via a bridging conjugate addition of the less nucleophilic b-ketoes-
metathesis
or
CO2Et
CO2Et
(Path A)
CO2Et
OH
N
sequential
oxidation-Wittig
olefination
8
CO2R
6
OH
OH
N
Wittig
olefination
6
CO2Et
2
Hydrolysis
(Path B)
N
O
and/or
R
O
oxidation
9
(12)
R = CH2OH (10)
CH2OTHP (11)
O
ter moiety to the deactivated a,b-unsaturated ester as the electro-
Scheme 4. Synthetic routes explored to prepare precursors 2.
philic alkene. Amine-catalysed intramolecular Michael addition
implying these both weakly reactive partners has never been stud-
ied up till now and still remains a great challenge. Indeed, an
organocatalysed procedure will provide a particular attractive
method for the synthesis of highly functionalized products in both
step- and atom-economical manner (Scheme 2).
only degradation products were obtained. Degradation may be ex-
plained by the competitive oxidative cleavage of the enol ester
function borne by the piperidine moiety. For this reason, prepara-
tion of the Wittig olefination precursor has been attempted by dif-
ferent strategies. Piperidinone 4 has been successfully alkylated by
2-(2-bromoethyl)-1,3-dioxolane, 3-bromopropoxy-tetrahydro-2H-
pyran and 3-bromopropan-1-ol in roughly 70% yields (Scheme
4—Path B—compounds 12, 11 and 10). Nevertheless, neither acidic
dioxolane cleavage of 12 nor oxidation of propanol derivative 10
followed or not by trapping with Wittig reagent allowed the
respective access to the aldehyde intermediate 9 or to precursor
2 (Scheme 4—Path B). Only degradation has been observed. These
results can be explained by the instability of the b-amino-aldehyde
intermediate 9 that may auto-condense through aldolization or
that may undergo retro-Michael reaction.
Due to these unsatisfactory results, the firstly envisaged N-
alkylation procedure using 5-bromo-2-pentenoate 5 has been
revisited. That was also sustained by the fact that the target com-
pound 2 and its deconjugate isomer 7 were gratifyingly separated
by flash chromatography on silica gel. The N-alkylation reaction
was then followed by 1H NMR: examination of the crude reaction
mixture spectrum revealed the formation of alkyl penta-2,4-dien-
ecarboxylate 13 resulting from base-mediated dehydrobromina-
tion of 5.19,20 As already known, N-alkylation proceeded, de facto,
In the first part of this current work, considerable efforts have
been made to optimize the synthesis of the cyclization precursors
2a (methylester) and 2b (benzylester) (Scheme 3). Their prepara-
tion was performed from the commercially available N-benzylated
piperidin-4-one hydrochloride 3 (Scheme 3). The latter was first
hydrogenolysed in the presence of Pearlman catalyst to afford
the piperidin-4-one hydrochloride 4 in quantitative yield.11 The
following step was first envisaged through direct alkylation of
the piperidine nitrogen-base by methyl or benzyl (E)-5-bromo-2-
pentenoate 5a or 5b.14 The latter have been prepared in excellent
90% and 65% yields, respectively with an exclusive E-selectivity
according to a one-pot two-step procedure. This strategy involves
in situ generation of 3-bromopropanal followed by Wittig olefin-
ation with methyl or benzyl (triphenylphosphoranylidene)acetates
6a or 6b respectively.15 Under standard basic conditions, N-alkyl-
ation step afforded in poor yields a mixture of the expected precur-
sor 2a or 2b as the minor product accompanied by its deconjugate
isomer 7a or 7b, respectively (Scheme 3).
Next, confronted to this undesired deconjugation reaction,
numbers of alternative synthetic routes have been explored and
are summarized in the retrosynthetic Scheme 4. Piperidinone 4
has been alkylated by 4-bromo-but-1-ene in 75% yield (Scheme
4-Path A). The corresponding N-homoallyl derivative 8 has been
then fruitlessly engaged in different synthetic sequences such as
(1) cross-metathesis in the presence of titanium isopropylate and
Grubbs II or Grubbs-Hoveyda catalyst;16 (2) cross-metathesis in
the presence of both previous catalysts from piperidine firstly
quartenarized by the action of benzylbromide;17 (3) oxidative
cleavage (ozonolysis or OsO4–NaIO418) followed by Wittig olefin-
ation using 6a or 6b (Scheme 4—Path A). Starting material was
recovered unchanged except in the oxidative cleavage in which
by an aza-1,6-conjugate addition producing both
a
,b- and b,
c-
unsaturated adducts 2 and 7, respectively:21 the b,
c-unsaturated
compounds 7 result from kinetic protonation of the intermediary
enolate.21b To improve the reaction efficiency, solvent and base ef-
fects were explored and the more significant results were summa-
rized in Table 1.
It was shown that reaction proceeded in poor yields using
potassium carbonate or triethylamine considered separately (en-
tries 1–4). Partial transesterification of the benzyl ester moiety oc-
curred using methanol as the solvent (entry 1). Reactions
performed at 25 °C using DMF were found optimal (entries 6–7).
Modest yields of this N-alkylation reaction are explained by direct
bridging annulation side-reaction of compound 2 occurring under
basic conditions. Indeed, trials of DBU-catalysed conjugative isom-
HBr(g)
O
erization21d of b,
c-unsaturated ester 7b furnished the targeted a,b-
Toluene
CO2R
R = Me 6a
Bn 6b
O
(Ph)3P
Br
Toluene
21°C
unsaturated isomer 2b in 50% yield after one day of reaction,
accompanied by 10% of the Michael adduct 1b. Prolonged reaction
time (3 days) effected cyclization and led in excellent 85% yield a
racemic mixture of 1-azabicyclononane 1b with good diastereo-
meric excess (de 75%) measured by 1H NMR (Scheme 5). The rela-
tive configuration of the major diastereomer 1b was ascertained by
2D and NOESY NMR experiments (Scheme 5 and Supplementary
data). Similar results of tandem conjugative isomerization-bridg-
ing Michael cyclization were observed starting from a mixture
7a/2a or 7b/2b in terms of selectivity and rate.
Br
CO2R
O
O
OH
Pd(OH)2
R = Me 5a (90%)
EtO2C
EtO2C
CO2Et
CO2R
H2, 5 bars
Bn 5b (65%)
MeOH-CH2Cl2
(5:1)
Et3N, MeOH
N
Bn
3
N
H
N
HCl.
HCl.
22 °C, 2 days
4
R= Me 2a/7a
99 %
Bn 2b/7b
Scheme 3. Synthesis of cyclization precursors.

3298
A. N. Ngo et al. / Tetrahedron Letters 53 (2012) 3296–3300
Table 1
Optimization of piperidin-4-one N-alkylationa
Br
CO2R
OH
N
OH
N
5a or 5b (1.2 eq.)
CO2Et
CO2Et
CO2R
O
+
Base solvent
EtO2C
CO2R
COOR
N
H
HCl.
R= Me 13a
Bn 13b
R= Me 2a
Bn 2b
R= Me 7a
Bn 7b
4
Entry
Basea
5
Solvent T (°C), t (d)
Yieldb (%)
1
2
3
4
5
6
7
K2CO3 5 equiv
K2CO3 5 equiv
K2CO3 5 equiv
Et3N 6 equiv
K2CO3 5 equiv + iPr2Net 3 equiv
K2CO3 1,5 equiv + Et3N 5 equiv
K2CO3 1,7 equiv + Et3N 3,6 equiv
5b
5b
5b
5b
5b
5a
5b
MeOH 25 °C, 2d
7a (20)
2b/7b (10/10)
—
7b (30)
—
CH2Cl2/THF (1/1) 24 °C, 2d
AcCN/THF (3/1) 50 °C, 3d
CH2Cl2/THF (2/1) 24 °C, 3d
CH2Cl2/THF (1/1) 24 °C, 3d
DMF 24 °C, 7d
7a/2a (42/33)
7b/2b (40/32)
DMF 24 °C, 7d
a
The reaction was carried out starting from a molar solution of piperidin-4-one hydrochloride 4.
Isolated yield.
b
mediated asymmetric Michael reaction,25,26 we wish to study the
straightforward synthesis of 1-azabicyclo[3.3.1]nonane skeletons
by unexplored organocatalysed intramolecular Michael addition
OH
N
OH
N
H
nOesy
BnO2C
H
CO2Et
CO2Bn
CO2Et
CO2Bn
H
DBU (10 mol%)
+
H
O
CH2Cl2
CO2Et
to a,b-unsaturated esters. The organocatalysed bridging conjugate
H
H
N
rt, 3 days
addition was first investigated starting from 2b using proline A,
proline derivatives (B–D) and Cinchona alkaloid-derived catalysts
E and F (Table 2). Whatever the reaction time (until 15 days) and
protic (EtOH) or aprotic (CH2Cl2 or CHCl3) conditions, organocata-
lysts A, B, C and D (10–30 mol %) were ineffective. Similarly, use of
both cinchonidine derivative E and dihydroquinine derivative F (5–
10 mol %) in basic phase-transfer catalysis (10 mol % of K2CO3 or
CsOH) was unsuccessful. In all cases, at room temperature, starting
material remained unmodified. Under refluxing conditions, only
degradation was observed. Satisfyingly, use of the bi-functional
catalyst proline-tetrazole B/piperidine led up to the expected aza-
bicyclononane 1b in 60% yield with total diastereoselectivity (entry
1). Furthermore, we have shown that piperidine used in stoichiom-
etric amount did not allow access to cycloadduct 1b starting from
the conjugate precursor 2b (entry 2). These results suggested that,
under these reaction conditions, piperidine did favour neither
intramolecular Michael addition contrary to DBU nor enamine for-
mation. More gratifyingly, same reaction conditions applied to
deconjugate substrate 7b afforded diastereoselectively bicycle 1b
in 55% yield through a tandem conjugative isomerization-intramo-
lecular Michael reaction (entry 3). Similarly, the bridged amine 1a
was obtained in 55% yield from 7a (entry 6). Moreover, microwave
irradiation (150 °C, 150 W) efficiently accelerated the tandem reac-
tion without erosion of diastereoselectivity: reaction time was
shortened from 10 days to 10 h (entry 4).
H
de 75%
2b
(Rac)-1b (80%)
7b
(10%)
Scheme 5. DBU-induced tandem conjugative isomerization-bridging annulation.
Ph Me
NH2
OH
N
Ph Me
BnO2C
O
H
CO2Et
1) ZnCl2, 1.2 eq
(0.1 M THF)
H
H
H
N
O
1.2 eq
BnO2C
CO2Et
µW, 150 W
N
OEt
THF, 1.2GPa
2d
2) AcOH 10%, rt
150°C, Toluene
2h
H
N
de > 95%
ee = 48%
BnO2C
2b or 7b
70%
1b
14b
60%
Scheme 6. Asymmetric Michael cyclization of chiral b-enaminoester.
Keenly encouraged by these results, we examined the asym-
metric intramolecular Michael reaction using chiral b-enaminoest-
er derived from (S)-(À)-phenylethylamine (Scheme 5).22,13
Treatment of b-ketoester 2b or 7b by a slight excess of (S)-(À)-
phenylethylamine in toluene under microwave irradiation pro-
moted not only the formation of the chiral b-enaminoester (S)-
14b in 70% yield but also the unexpected conjugate isomerization
of the nitrogen-substituted lateral chain (Scheme 6).23 It has been
well established that Michael addition of chiral b-enaminoesters
required further activation by addition of Lewis acid or high pres-
sure in order to achieve reasonable yields and selectivity.24,22c At-
tempts to catalyse the cyclization of 14b with FeCl3, ZnCl2 And
Cu(OAc)2 (0.1–1.2 equiv) not only under standard thermal condi-
tions but also under microwave irradiations were unsuccessful.
Only the combined effects of stoichiometric amount Lewis acid
(ZnCl2, 1.2 equiv) associated to high pressure (1.2 GPa) activations
followed by hydrolytic work-up furnished diastereoselectively the
desired Michael adduct 1b in 60% yield (over two steps) and 48% ee
(Scheme 6). The excellent diastereocontrol can be justified by a
‘syn-periplanar’ approach of the two reactive parts with an ‘endo-
arrangement’ in which ester group of the acceptor part faced amine
of the b-enaminoester part (Scheme 6).
Chiral HPLC confirmed the excellent reaction diastereoselectiv-
ity but unfortunately showed the absence of enantioselectivity
suggesting that the relative bulkiness of secondary-amine catalysts
A–D may disfavour the formation of iminium ions with b-ketoest-
ers. The absence of facial differentiation by the chiral organocata-
lyst was able to explain this lack of enantioselectivity. In
conclusion, the secondary-amine catalysts, successfully used in
the asymmetric Michael reactions by Jørgensen,25 proved to be
inefficient for the stereocontrol of the intramolecular Michael addi-
tion of poor nucleophilic b-ketoesters to less electrophilic
a,b-
unsaturated esters. The excellent diastereocontrol can be justified
by the same approaches described previously starting from chiral
b-enaminoester (Scheme 6). The proline-tetrazole B/piperidine
catalyst might both stabilize the ‘endo-arrangement’ by hydro-
gen-bonding and authorize the 1,4-addition by external hydro-
gen-transfer.
Encouraged by the excellent diastereoselectivity and promising
enantioselectivity and by recent reports on organocatalyst-

A. N. Ngo et al. / Tetrahedron Letters 53 (2012) 3296–3300
3299
Table 2
Organocatalysed intramolecular Michael reaction screening
OH
OH
RO2C
H
CO2Et
CO2Et
CO2R
or/and
Organocatalyst
solvent, time
O
CO2Et
CO2R
N
N
N
R= Me 1a
Bn 1b
R= Bn 2b
R= Me 7a
Bn 7b
CF3
TMSO
Ph
Ph
OTMS
N
Cl
N
N
N
COOH
N
H
N
H
N
H
N
N
HN
H
C
CF3
CF3
Bn
A
OH
B
D
E
F3C
[DHQ]2PHAL
F
Entry
Compd
Catal.a (mol %)
Solvent T (°C), t (d)
Yieldb,c (%)
ded (%)
1
2
3
4
5
6
2b
2b
7b
7b
7b+2b
7a
B (15)
/
B (15)
B (15)
B (15)
B (15)
Piperidinee, CHCl3 22 °C, 7d
Piperidinee, CHCl3 22 °C, 7d
Piperidinee, CHCl3 22 °C, 10d
60c
S.M.f
55c
50c
63c
55c
>95
>95
>95
>95
>95
Piperidinee, CHCl3 Wf (150 °C), 10 h
l
Piperidinee, CHCl3 22 °C, 10d
Piperidinee, CHCl3 22 °C, 10d
a
b
c
d
e
f
Reactions were performed with substrate (0.5 mmol), catalyst and anhydrous solvent (0.1 mL).
Isolated yield.
100% conversion monitored by 1H NMR (disappearance of ethylenic proton).
de values were determined by 1H NMR and confirmed by chiral HPLC analysis.
0.5 mmol of piperidine was added.
Starting material.
5. (a) Ben Ayad, O.; Leclerc, O.; Lochead, A.; Saady, M.; Ben Slowinski F., Vache, J.
PCT Int. Appl. WO 2008110699, 2008.; (b) Slowinski, F.; Ben Ayad, O.; Vache, J.;
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In conclusion, the present work provides the first diastereose-
lective synthesis of highly functionalized 1-azabicyclo[3.3.1]non-
ane skeletons by an amine-mediated tandem conjugative
isomerization-intramolecular Michael addition. This concise strat-
egy exemplifies the not yet explored C-5/C-6 disconnection. More-
over, we have shown that the combined use of ultra-high pressure
and Lewis acid can circumvent the problems of substrate-depen-
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Acknowledgments
The authors are grateful to K. Leblanc for performing microanal-
yses and HPLC analyses and to C. Troufflard for NMR experiments.
The authors thank the University Paris-Sud for the grant of A.N.N.
The University Paris-Sud 11, the French Ministry of Superior Edu-
cation and Research and the CNRS are gratefully acknowledged
for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.04.069.
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300 MHz) H2 (5.85, d); H3 (7.20, dd), H4 (6.33, td), 2 Â H5 (5.42, dd).
20. In the absence of additional base, treatment of piperidin-4-one amine base 4
with alkyl bromopentenoate 5a or 5b only gives alkyl penta-2,4-diene-
carboxylate 8a or 8b.
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