Microwave-assisted telescoped cross metathesis-ring closing aza-Michael reaction sequence: step-economical access to nicotine-lobeline hybrid analogues

Article abstract of DOI:10.1039/c5ra20930g

A series of 2,5-disubstituted pyrrolidines was synthesized through an efficient telescoped cross-metathesis/cyclizing aza-Michael addition involving N-heteroaromatic olefinic derivatives. This synthetic route was applied to the preparation of original nicotine-lobeline, nicotine-pelletierine and lobeline-nicotine-epibatidine hybrids.

Full text of DOI:10.1039/c5ra20930g

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Microwave-assisted telescoped cross metathesis-ring closing aza-
Michael reaction sequence: a step-economical access to nicotine-
lobeline hybrid analogues
Received 00th January 20xx,
Accepted 00th January 20xx
E. Drège,a J. Oko,a P.-E. Venot,a N. Giganta and D. Josepha,†
DOI: 10.1039/x0xx00000x
www.rsc.org/
A series of 2,5-disubstituted pyrrolidines was synthesized through
an efficient telescoped cross-metathesis/cyclizing aza-Michael
addition involving N-heteroaromatic olefinic derivatives. This
synthetic route was applied to the preparation of original
nicotine-lobeline, nicotine-pelletierine and lobeline-nicotine-
epibatidine hybrids.
Introduction
Nicotinic acetylcholine receptors (nAChRs) belong to the family
of pentameric ligand-gated channels. As they play a significant
role in cognitive and sensory gating processes, nAChRs
comprise potentially therapeutic targets in manifold brain
disorders.1 One of the major challenges in drug discovery
targeting nAChRs, is to develop compounds that can
selectively bind one receptor subtype. If fragment-based
approach to find out selective receptor ligands is nowadays
widely established in drug discovery and chemical biology, the
application of this concept on nAChRs is delayed due to the
lack of readily available structural information and sensitive
biophysical screening methods. Only one fundamental
example of a fragment merging optimization of ligand has
been described for the acetylcholine binding protein, a model
Figure 1. Naturally occurring nAChR ligands and nicotine-lobeline hybrid analogues 5
economical synthetic processes of new Lobelia alkaloids
analogues as ligands of nAChR-subtypes.4 In the context of
targeting
α4β2-subtype, the synthesis of hybrid molecules
appeared to us as an interesting challenge and we decided to
investigate the preparation of original lobeline-natural nAChR
ligands chimeric analogues
pharmacophores (Figure 1).
5 by connecting relevant
A key advantage of the concept of molecular hybridization is
its capacity to create highly chemically diverse molecules with
a high degree of congenital resemblance, an essential criterion
for relevant structure-activity relationship studies. We thus
made an effort at designing a diastereoselective synthetic
pathway that could rapidly reach structural and functional
diversity. The shortness and the flexibility of this synthetic
strategy will be insured by a cross metathesis-ring closing aza-
Michael (CM-RCAM) sequence (Scheme 1).
protein for the extracellular
α
7 nAChR-subtype domain.2
Therefore, the concept of molecular hybridization continues to
be an alternative answer to find out new nAChRs ligands. More
potent and selective ligands have been developed by
combining the pharmacophores of natural alkaloids that
exhibit a pronounced nAChR pharmacological activity such as
O
nicotine (1), epibatidine (2), anatoxine (3) and lobeline (4)
(Figure 1).3
R3
NBoc
R2
+
N
CM-RCAM
COR3
R1
N
R2
R1
A part of our research program aims at shaping new step-
N
5
6
7
a. Université Paris-Sud, BioCIS, Equipe de Chimie des Substances Naturelles,
Université Paris-Saclay 5, rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry,
France.
† Corresponding author E-mail: delphine.joseph@u-psud.fr
R2NH2
+
O
OH
R1
N
R1
N
10
8
9
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Retrosynthetic strategy for the preparation of hybrids 5
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One of the challenges of our approach lies in the cross- As the transformation of the azide function appeared to be
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DOI: 10.1039/C5RA20930G
N-heteroaromatic-containing olefinic quite problematic, an alternative synthetic pathway was
metathesis of tethering
substrates
partners
6
with sensitive electron-poor olefinic coupling investigated. In this way, we evidenced that the mesylate 11a
7.
Retrosynthetic analysis suggests that the easily underwent nucleophilic substitution (SN2) in the
transformation of the hydroxyl group of
function could easily lead to the formation of the key CM- the pentenamine 14a in a satisfying 60% yield. The yield was
RCAM precursors . It was further expected that the synthesis increased to 75% by using a 2M THF solution of methylamine
of the alcohol would be secured by the condensation and 3- rendering the purification step simpler as well. These
butenylmagnesium
carboxaldehydes 10
8 into an amine presence of aqueous methylamine in DMF at 60 °C, affording
6
8
bromide
with
2-substituted-5- amination conditions were also successfully applied to 11b
delivering 14b in a good 70% yield. Nonetheless, a longer
.
We present herein a short and efficient access to nicotine- reaction time was necessary to reach full conversion: four days
natural nAChR ligand hybrids for which each synthesis step were needed for 14b instead of twelve hours in the case of
offers both diversity and flexibility with three distinct sites of 14a suggesting a deactivating effect of the chlorine atom on
modulation (R1, R2 and R3) and involves simple and the nucleophilic substitution. Interestingly, it must be pointed
commercially available precursors (
7,
9
and 10).
out that these N-methyl-pent-4-en-1-amines 14 did not
require any further purification, before being engaged in the
following step, highlighting the synthetic process cleanliness.
At this stage of our synthesis, the protection of the
methylamine group of 14 by an electron-withdrawing group
was envisaged to avoid potential deactivating coordination
between the amine function by the ruthenium-based catalyst
Results & discussion
Our synthetic efforts are depicted in Scheme 2 and started
with the efficient preparation of the pent-4-en-1-ol 8a and 8b
.
The olefinic Grignard reagent was easily prepared starting
from 4-bromo-1-butene in the presence of magnesium before
reacting with the commercially available pyridine-3-
carboxaldehyde 10a or 6-chloropyridine-3-carboxaldehyde
during the olefin cross-metathesis (CM).
N-Methylamines 14
were thus treated with Boc2O providing the advanced key
intermediates 6a and 6b in high yields (90% and 75%,
respectively).
10b.5 The hydroxyl function of the pyridinic pentenols
8 was
Only few examples of tandem CM/aza-Michael process have
already been reported in the literature.4c,8 The bibliography
becomes particularly poor for substrates bearing a strong
Lewis base such as a free amine or a pyridine that may
dramatically deactivate the catalyst.9 To the best of our
knowledge, the reactivity of these potentially metal-
coordinating substrates has never been described in the
then efficiently transformed in a leaving group by mesylation
under standard conditions. The mesylates 11a and 11b were
isolated without further purification in 96% and 92% yields,
respectively. Our initial attempts to synthesize the required
amine moiety were envisaged via a two-step sequence
including the introduction of an azido group followed by its
reduction into primary amine. Treatment of the mesylated
derivative 11a with sodium azide led to the desired azide 12a
in a 80% yield. Unfortunately, the Staudinger reduction of 12a
under usual conditions failed, giving a complex mixture of
products. In the same way, other methods for converting an
azido group into an amine function using propane-1,3-dithiol,6
or indium metal and ammonium chloride7 gave a mixture of
inseparable polar products.
presence of electronically biased olefins, such as
α,β-
unsaturated ketones. Following our recent results in this
field,4c we decided to screen the efficiency of five commercially
available Ru complexes (Figure 2). These pre-catalysts were
selected based on their catalytic features: three standard
metathesis complexes such as the Grubbs 2nd generation I (G-
II),10a the Grubbs-Hoveyda 2nd generation II (GH-II)10b and the
indenylidene-based complex III (M2);10c and two well-defined
fast-initiation Hoveyda-type complexes bearing either a SIMes
(
IV) or a SIPr (V
) NHC unit.11
Scheme 2. Reagents and conditions for the synthesis of 4-penten-1-amines 6a and 6b:
(a) CH2=CHCH2CH2MgBr, THF, -20 °C to rt; (b) MsCl, Et3N, CH2Cl2; (c) NaN3, DMF; (d)
MeNH2, DMF, H2O, or MeNH2 (2 M, in THF) 50 °C; (e) Boc2O, Et3N, CH2Cl2.
Figure 2. Screened ruthenium-based metathesis
2 | J. Name., 2015, 00, 1-3
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We first evaluated the feasibility of this reaction by submitting Phenyl vinyl ketone12 7d was next submitted to cross-
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6 with methyl acrylate metathesis with the terminal alkene 6a (Table 1, entries 8-11).
the pyridinic olefinic derivatives 14 and
7a or ethyl acrylate 7b. As earlier described by the group of The reaction was particularly reluctant under conventional
Cossy on pyridinic homallylic alcohols,9a the CM involving the heating conditions and did not work whatever the catalyst
pyridinic olefinic amine 14a in the presence of the Grubbs used. Contrastingly, the coupling product 15ad was easily
catalysts
I or II (10 mol %) in refluxing dichloromethane for obtained in a modest 50% yield, in only 3 hours combining
24 h only permitted the recovery of the starting material. microwave irradiation with GH-II catalyst II (Table 1, entry 8).
These results were in coherence with the known poisonous Remarkably, following fully optimized conditions (i.e. 7.5 mol%
character of both the amine and the pyridine substituents of the precatalyst IV, 1 h of microwaves irradiation), the
which deactivate the ruthenium catalyst by coordinating the expected product 15ad was produced in a 70% yield (Table 1,
metal centre.9b The study was thus pursued using the pyridines entry 10). This protocol was finally extended to the more
6a and 6b and our results are summarized in Table 1. In this reactive chloropyridine scaffold 6b, and very satisfyingly, the
way, starting from the
desired cross-coupled product 15aa was formed in an a complete
encouraging 55% yield in the presence of the 2nd generation result was in accordance with the demonstrated favourable
Grubbs catalyst under the same aforementioned reaction effect of a chlorine electron-withdrawing C-2 substituent that
conditions (Table 1, entry 1). The use of GH-II catalyst (II
reduces the Lewis basicity of the pyridinic nitrogen atom.9a
N
-Boc protected derivative 6a, the highly functionalized Michael acceptor 15bd was isolated with
E
selectivity in a 90% yield (Table 1, entry 11). This
I
)
provided the CM product 15aa in an enhanced 60% yield even With the precursors 15 in hands, we focused on the cyclising
with a lower 5 mol% catalyst loading (Table 1, entries 2-3). aza-Michael step. Even though amino-enone 15ab underwent
Moreover, the reaction time was dramatically reduced from Boc-deprotection in the presence of a catalytic amount of HCl
24 h to 45 min or 60 min when microwave heating was in i-PrOH at 60 °C, the RCAM did not occur. Pleasingly,
employed (Table 1, entries 1-3). Interestingly, yields were microwave heating (100 °C, 200 W) efficiently reached the
improved up to 70% by using more hindered catalysts such as whole cascade in only 45 min, yielding the targeted
IV or
V
with ethyl acrylate 7b as olefinic partner (Table 1, pyrrolidines 5ab and 5ac in 50% to 65% yields (Scheme 3, eq
1). In addition, the best conditions for the tandem
entries 4-6).
Encouraged by these successful results with alkyl acrylates, we deprotection-cyclization sequence applied to 15ad were
next examined the less studied cross-metathesis coupling with reached under ultrasound exposure for 3 hours and to 15bd by
several vinyl ketones. Starting from methyl vinyl ketone 7c, the using conventional heating at 80 °C for 2 hours.
desired enone 15ac was isolated in a good 70% yield by In our continuing interest for developing economically
combining the GH-II catalyst II with microwave irradiation favorable synthetic procedure, we surmised that the
(Table 2, entry 7).
sequential CM/RCAM process could be telescoped. Indeed,
Fustero and co-workers reported diastereoselective domino
cross-metathesis/aza-Michael reaction catalyzed by ruthenium
complexes with Lewis acid as co-catalyst for the synthesis of
piperidine, pyrrolidine and lactam derivatives.8c,e-f Directly
applied to our pyridinic olefins, the cascade process using
Table 1: Optimization of the cross-metathesis of pyridine with electron-poor olefinic
partners.
either Ti(OiPr)4 or BF3·OEt2 as Lewis acid co-catalyst failed,
providing complete degradation of the starting materials. To
our delight, under microwave irradiation, sequential addition
of a catalytic amount of concentrated hydrochloric acid after
the cross-metathesis completion (controlled by TLC), initiated
µwaves
cat.
thermal
yieldb (%)
Entry R1
R2
Product
yieldb (%)
(time)
the
N-Boc clivage and activated the subsequent aza-Michael
(mol%)
induced ring closure.
1
2
H
H
H
H
H
H
H
H
H
H
Cl
OMe
OMe
OMe
OEt
OEt
OEt
Me
Ph
I (10)
II (10)
II (5)
15aa
15aa
15aa
15ab
15ab
15ab
15ac
15ad
15ad
15ad
15bd
55
60
60
-
65 (1 h)
70 (1 h)
3
70 (45 min)
30 (3 h)
4c
5c
6c
7
III (10)
IV (5)
V (5)
-
70 (45 min)
70 (45 min)
70 (1 h)
-
II (5)
50
SMd
-
SMd
8
II (5)
50 (3 h)
9c
10
11c
Ph
III (5)
IV (7.5)
IV (5)
10 (3 h)
Ph
70 (1 h)
Ph
-
90 (1 h)
a Conditions: 1 equiv 6a or 6b, 1.3 equiv 7a-7d, CH2Cl2 (0.5 M), reflux, 24 h or, 100
c
°C µwaves (200 W). b Isolated yield. The reactions were only performed under
microwave irradiation.d Starting material.
Scheme 3. RCAM reaction and telescoped CM-RCAM reaction.
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Journal Name
M. N. Romanelli, P. Gratteri, L. Guandalini, E. Martini, C.
Bonaccini and F. Gualtieri, ChemMedChem.,
E. Edink, P. Rucktooa, K. Retra, A. Akdemir, T. Nahar, O.
Zuiderveld, R. van Elk, E. Janssen, P. van Nierop, J. van
Muijlwijk-Koezen, A. B. Smit, T. K. Sixma, R. Leurs, I. J. P. de
Extension of these optimized conditions provided the isolation
View Article Online
DOI: 102.1000397/,C25,R7A42609. 30G
of the original pyrrolidines 5ab, 5ac, 5ad and 5bd in 50-70 %
2
3
yields over three steps (Scheme 3, eq 2). More in details, a
mixture of both diastereomers was obtained. If the 2,5-cis
diastereoisomer was kinetically favoured, it rapidly
equilibrated in solution toward the thermodynamically more
stable 2,5-trans epimer through a well-known auto-catalyzed
retro-aza-Michael/aza-Michael cyclization process.4d The
relative configuration of the major diastereoisomer was
established by nOesy experiments and revealed a trans
configuration between the both hydrogen atoms of the
pyrrolidine C-2 and C-5 atoms (Scheme 3, eq 2).
Esch, J. Am. Chem. Soc., 2011, 133, 5363.
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Wonnacott, J. Org. Chem., 2003, 68, 2475; (b) E. Wright, T.
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9231; (d) W. Hatton, F.-X. Felpin, M, Evain, M. Mathé-
Allainmat and J. Lebreton, Synlett, 2010, 11, 1631.
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b
Conclusions
c
d
We shaped a synthetic pathway allowing a short and efficient
access to a series of lobeline-nicotine, pelletierine-nicotine and
lobeline-nicotine-epibatidine hybrids. More generally, we
demonstrated that this approach based on a challenging
Amara, G. Bernadat, P.-E. Venot, P. Retailleau, C. Troufflard,
E. Drège, F. Le Bideau and D. Joseph, Org. Biomol. Chem.,
2014, 12, 9797; (e) E. Drège, P.-E. Venot, F. Le Bideau, P.
Retailleau and D. Joseph, J. Org. Chem., 2015, 80, 10119.
The starting material was prepared on a 10 g scale and used
without purification according to a known procedure, see: J.
B. Summers, S. K. Davidsen, D. H. Steinman, J. G. Phillips, M.
B. Martinand and D. E. Guinn, US Pat., 5149704, 1992.
5
6
monotope
sequential
microwave-mediated
cross-
metathesis/cyclizing aza-Michael reaction is expandable to the
diastereoselective preparation of 2,5-trans disubstituted
pyrrolidines. This synthetic strategy has the advantages of (i)
involving simple starting reagents and available Ru-
precatalysts, (ii) producing several purification-free synthetic
intermediates and (iii) facilitating the introduction of
molecular diversity. Moreover, the developed methodology
enabled, under microwave irradiation, the telescoping of the
cross-metathesis and the intramolecular aza-Michael reaction
into a single efficient process, readily amenable to scale up.
New applications of this strategy for the enantioselective
synthesis of pyrrolidines as well as the nAChR-subtypes binding
affinity and activity of selected nicotine-lobeline hybrid
analogues are currently in progress and will be reported in due
course.
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Acknowledgments
a
,
1
b
The authors are indebted to Oméga Cat System Company for
the generous gifts of ruthenium catalysts. The authors are
grateful to Claire Troufflard and Karine Leblanc for performing
respectively NMR experiments and elemental analyses. The
authors thank the University Paris-Sud for the grant of P.-E. V.
The University Paris-Sud, the LabEx LERMIT, the French
Ministry of Higher Education and Research and the CNRS are
gratefully acknowledged for their financial support.
c
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Step-economical access to nicotinic acetylcholine receptor ligands hybrids through an efficient telescoped cross-
metathesis/cyclizing aza-Michael addition involving N-heteroaromatic olefinic derivatives.