A hydrozirconation/iodination-mediated access to tetrahydroquinolizinium salts. Application to the synthesis of Lupinine and (-)-Epiquinamide

Article abstract of DOI:10.1016/j.tetlet.2012.12.073

The preparation of tetrahydroquinolizinium salts, based on a hydrozirconation/iodination sequence involving 2-pyridyl alkenes, is presented. This approach was applied to the synthesis of substituted quinolizines as illustrated by the synthesis of Lupinine

Full text of DOI:10.1016/j.tetlet.2012.12.073

Tetrahedron Letters 54 (2013) 1029–1031
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A hydrozirconation/iodination-mediated access to tetrahydroquinolizinium
salts. Application to the synthesis of Lupinine and (ꢀ)-Epiquinamide
⇑
Majdi Hajri, Clément Blondelle, Agathe Martinez, Jean-Luc Vasse , Jan Szymoniak
Institut de Chimie Moléculaire de Reims, CNRS-UMR 6229, Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of tetrahydroquinolizinium salts, based on a hydrozirconation/iodination sequence
involving 2-pyridyl alkenes, is presented. This approach was applied to the synthesis of substituted
quinolizines as illustrated by the synthesis of Lupinine and (ꢀ)-Epiquinamide.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 November 2012
Revised 17 December 2012
Accepted 19 December 2012
Available online 28 December 2012
Keywords:
Alkaloids
Hydrozirconation
Tetrahydroquinolizinium salts
Lupinine
(ꢀ)-Epiquinamide
A source of inspiration for the design of biologically active syn-
thetic molecules, naturally occurring alkaloids constitute a funda-
mental class of molecules.1 Among them, the quinolizidine series
is one of the more important families of alkaloids, exhibiting a
broad range of biological activities.2 In this context, the develop-
ment of a new approach toward the quinolizidine framework, val-
idated through the synthesis of known alkaloids, might provide
tools for the design of analogs.
Several strategies toward the quinolizidine framework are
based on the cyclization of 2-substituted piperidine. Among them,
the emerging strategies are the ring-closure metathesis,2b,3 the
reductive amination,4 the condensation,5 and SN2 type reactions.6
Additionally, the construction of quinolizidine skeleton via an
In this Letter, we wish to report the diastereoselective synthesis
of Lupinine, isolated from Lupinus spp.12 and (ꢀ)-Epiquinamide,
enantiomer of the naturally occurring alkaloid isolated from the
skin of poisonous Ecuadorian frog Epipedobates tricolor13 (Fig. 1).
Our approach toward the quinolizine skeleton was initiated by
first investigating the pyridinium formation. Model substrate 114
underwent hydrozirconation with the Schwartz reagent, then
NCS was added to give the chloro pyridine 2. The corresponding
salt was obtained in refluxing EtOH, and was directly submitted
to PtO2-catalyzed hydrogenation to afford the quinolizine 3 as a
3:1 mixture of diastereomers. For a direct formation of the salt,
the sequence was modified by adding I2 in place of NCS, to give
the iodide salt 4. Under the same hydrogenation conditions, 3
was obtained as a 9:1 mixture of diastereomers (Scheme 1). The
major isomer 3-syn15 was isolated in pure form by purification
on alumina in 56% yield.
aza-Diels–Alder reaction7 or
a gold-catalyzed formal [4+2]
approach was also reported.8 Alternatively, intramolecular
pyridine quaternarization followed by hydrogenation, is a straight-
forward way to prepare functionalized quinolizidines9 and indo-
lizidines.10 Moreover, this strategy proceeds stereoselectively in
most cases, owing to the rigidity of the substrate.
X
Recently, we reported an efficient synthesis of pyrrolidines via a
hydrozirconation/iodination sequence,11 and we thought if this
was applied to pyridine bearing an unsaturated chain at the
2-position, a similar cyclization might occur. It would lead to
quinolizinium salt, thus opening the way to the diastereoselective
synthesis of quinolizidines (Fig. 1).
N+
1) Cp2Zr(H)Cl
2) "X+"
N
N
X-
R
R
R
R
Hydrogenation
N
N
N
H
H
H
H
N
Ac
OH
epiquinamide
lupinine
⇑
Corresponding author. Tel.: +33 3 2691 3431; fax: +33 3 2691 3166.
E-mail address: jean-luc.vasse@univ-reims.fr (J.-L. Vasse).
Figure 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.073

1030
M. Hajri et al. / Tetrahedron Letters 54 (2013) 1029–1031
Cl
1) LDA, THF
then
Br
N
N
Cp2Zr(H)Cl, CH2Cl2
N
Cp2Zr(H)Cl
N
N
H
1) EtOH, Δ
2) DIBAL-H, THF
then I2
78%
2) H2, cat PtO2
then NaOH
42%
then NCS
82%
CO2Me
3) TBDMSCl,
9
TBSO
Ph
Ph
Ph
2
Imidazole, DMF
1
10
3
60%
TBAF, THF
81%
Cp2Zr(H)Cl
then I2
80%
dr = 3 : 1
N+
1) H2, cat PtO2
, MeOH
N
N
H
N+
H2, cat PtO2
N
H
I-
H
2) aq NaOH
N
I-
H
Ph
then NaOH
dr = 9 : 1
63%
TBSO
TBSO
HO
( )-Lupinine
H
NOE
Ph
Ph
d.r = 5.5 : 1
4
11
12
3-syn (56%)
Scheme 3.
Scheme 1.
Br
1)
In, MeOH
The improvement of selectivity observed when using 4 as the
substrate, may originate from the size of the counter anion. Indeed,
the dipolar interactions between the tetrahydroquinolizinium and
its counter anion are likely to differ from the chloride to the iodide.
This may result in a more effective facial discrimination of the
pyridinium in the case of the iodide salt 4.
The next stage of the study was to prepare a hydroxy function-
alized quinolizine. At first, we decided to avoid the direct use of
alcohol, since one sacrificial equivalent of hydride would be con-
sumed by the hydroxyl group, and opted for the tert-butyldimeth-
ylsilyloxy group. This choice was also aimed at increasing the
quinolizinium solubility in organic media.
The hydrozirconation/iodination sequence was applied to 6,
prepared in classical conditions from the known alcohol 5. The salt
7 was isolated in 77% yield. Subsequent hydrogenation afforded
the quinolidizine 8 in 90% yield as a single stereoisomer according
to NMR analysis (Scheme 2).
N
Ac2O or Boc2O
Et3N, CH2Cl2
N
N
OH
2) TBDMSCl
3) separation
4) TBAF
5) Pb(OAc)4
then NH2OH.HCl
NH2
N
NHPG
14
15, PG = Ac, 98%
16, PG = Boc, 70%
13
Ph
er >98:2
52%
N+
N
1) H2, cat PtO2
,
MeOH
Cp2Zr(H)Cl
then I2
N
H
I-
2) aq NaOH
HN
HN
HN
63%
Boc
Boc
dr = 2.2 : 1
Boc
18-syn (37%)
16
17
Scheme 4.
The strategy was then slightly modified by choosing a bulky Boc
protection, that was less prone to reduction.20 In this case, two
equivalents of Schwartz reagent were necessary to perform the
complete C@C hydrozirconation of 16,19 one being consumed by
the carbamate. Subsequent addition of iodine led to the expected
salt 17, which was contaminated by zirconocene side-products.
Repeated washings did not allow isolation of the salt in satisfactory
purity. Subsequent PtO2-catalyzed hydrogenation gave the satu-
rated bicycle 1821 as a 2.2:1 mixture of diastereoisomers. Purifica-
tion by column chromatography allowed the isolation of the major
syn product in 37% yield (Scheme 4).
Our attention was next focused on the synthesis of Lupinine and
Epiquinamide, two natural alkaloids incorporating, respectively a
CH2OH and a NHAc fragment, at the same position with the iden-
tical relative configuration.
The synthesis of Lupinine,16 was performed by applying the
quaternarization sequence to silylether 10. The resulting salt 11
underwent PtO2-catalyzed hydrogenation to provide Lupinine pre-
cursor 12, as a 5.5:1 mixture of diastereomers. The major isomer
12 was isolated in 63% yield by column chromatography, and next
treated with TBAF to afford racemic Lupinine (Scheme 3). The spec-
tral data were identical with those reported in the literature.16a
In the case of Epiquinamide,3a,b,16a,b,17 a non-racemic synthesis
was envisioned. The indium-mediated diastereoselective allylation
of 13,18 proceeded in a 96:4 dr. The alcohol protection allowed an
efficient separation of the two diastereomers. Subsequent depro-
tection and oxidative removal of the chiral auxiliary residue18 gave
the enantiomerically enriched amine 14.19 The access to the quin-
olizinium salt was first planned from 15, which directly incorpo-
rates the required NHAc group. However, the competing
reduction of the amide occurred during the hydrozirconation.
We next decided to prepare the corresponding diBoc22 analog
19 to, limit the amount of the Schwartz reagent and, facilitate
the isolation. The corresponding salt 20 was obtained by using
1.2 equiv of hydride followed by the addition of I2 (1 equiv) and
isolated without zirconocene impurities. In this case, quinolizidine
22 was obtained in two steps using NaBH4,23 to give 21 as a 20:1
mixture of diasteroisomers in favor of the desired syn isomer.
N+
Cp2Zr(H)Cl
then I2
N
n-BuLi, THF
N
I-
then Boc2O
TBSCl, Imidazole
Cp2Zr(H)Cl, CH2Cl2
N
N
N(Boc)2
N(Boc)2
20
NHBoc
19
79%
86%
16
DMF
81%
NaBH4,
MeOH
then I2
77%
93%
5
OH
OTBS
6
H2, Pd/C
N
H
1) HCl, MeOH
N
H
N
N+
1) H2, cat PtO2, MeOH
N
H
I-
MeOH
82%
2) Ac2O, Et3N
86%
H
N(Boc)2
dr 20 : 1
N(Boc)2
HN
2) aq NaOH
90%
21
Ac
(-)-Epiquinamide
22
OTBS
OTBS
7
8
Scheme 2.
Scheme 5.

M. Hajri et al. / Tetrahedron Letters 54 (2013) 1029–1031
1031
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Subsequent Pd-catalyzed hydrogenation afforded 22. Finally,
deprotection and acylation gave the target (ꢀ)-Epiquinamide in
86% yield, ½a 2D0
ꢁ
ꢀ23, (c 1.25, CHCl3), lit.17a: +24 (c 0.1, CDCl3) for
the (S,S) enantiomer (Scheme 5).
In summary, the access to tetrahydroquinolizinium salts involv-
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pyridine was described.24 This approach opens the way to the dia-
stereoselective preparation of substituted quinolizidines as illus-
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Acknowledgment
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CH2Cl2 (3 mL) was added in one portion Cp2Zr(H)Cl (310 mg, 1.2 mmol), and
the reaction mixture was stirred until complete dissolution (ca 20 min). I2
(254 mg, 1 mmol) was added and the stirring was continued for 20 min. Water
(5 mL) was added and the biphasic mixture was stirred for 1 h. The organic
layer was washed with water (5 mL), dried over MgSO4 filtrated and
concentrated under reduced pressure. The residue was washed with
cyclohexane to give the corresponding salt which was used directly in the
hydrogenation step.
Financial support of this work by the CNRS is gratefully
acknowledged.
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.
12.073.
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