Angewandte
Chemie
DOI: 10.1002/anie.201306656
Heterocycles
Enantioselective Organocatalytic Multicomponent Synthesis of 2,6-
Diazabicyclo[2.2.2]octanones**
Maria del Mar Sanchez Duque, Olivier Baslꢀ, Yves Gꢀnisson, Jean-Christophe Plaquevent,
Xavier Bugaut,* Thierry Constantieux,* and Jean Rodriguez
Multicomponent reactions consist of the combination of at
least three different partners in a domino sequence which
occurs without any modification of the reaction conditions.[1]
They represent powerful multiple bond-forming transforma-
tions for the fast construction of complex structures which are
not easily synthesized by traditional stepwise strategies.[2]
With the increased focus on the preparation of enantiopure
compounds, recent efforts have been directed towards the
development of enantioselective multicomponent reactions.[3]
However, the potential interference of the third reactant
during the enantioselective combination of the two other
reaction partners adds complexity when compared to enan-
tioselective two-component processes. Pioneering work by
Enders and co-workers illustrated how a prolinol derivative
can be used to control the chemo- and enantioselective
assembly of three different reaction partners.[4] Since then,
organocatalysts, which have high functional-group tolerance
and operate under mild reaction conditions, have appeared as
the most suitable tools for promoting enantioselective multi-
component reactions.[5]
During the course of our studies directed towards the
development of multicomponent reactions from 1,3-dicar-
bonyls to access highly elaborated polycyclic molecules,[6] the
highest level of complexity was reached in 2005, when our
group reported the Michael addition initiated three-compo-
nent reaction of b-ketoamides, acrolein, and an amine
functionalized with a pendant nucleophile. The three starting
materials were combined in refluxing toluene in the presence
of 4 ꢀ molecular sieves to afford the structurally complex 2,6-
diazabicyclo[2.2.2]octanone (2,6-DABCO) core in good yield
[Eq. (1); M.S. = molecular sieves].[7] Noteworthy is that five
new bonds[8] were created during this Michael addition/
double iminium trapping sequence and three stereocenters
were installed with complete diastereoselectivity, with the
production of two molecules of water as the only by-product.
Later, we showed that replacing toluene by an ionic liquid
could broaden the scope of the reaction.[9]
However, to valorize these original structures, it would be
helpful to obtain them under enantioenriched form. The main
challenge to develop a catalytic enantioselective synthesis of
2,6-DABCOs is to find reaction conditions which are suitable
both for the enantioselective Michael addition of a b-ketoa-
mide with an enal and for the subsequent iminium trappings.
The enantioselective Michael addition of 1,3-dicarbonyls is
arguably one of the most studied organocatalytic trans-
formations.[10] However, the use of this elemental step as the
enantiodetermining one in multicomponent sequences still
remains scarce in the literature.[11]
We report herein our efforts towards the development of
an enantioselective synthesis of 2,6-DABCOs under bifunc-
tional organocatalysis.[12,13] This also constitutes a proof of
concept that very complex transformations are amenable to
enantioselective control by hydrogen-bonding activation,
even in the presence of substrates containing acidic hydrogen
atoms. The targeted bridged pentacyclic scaffolds[14] were
obtained in excellent chemical yields along with high enantio-
and diastereoselectivities by assembling three simple poly-
functionalized starting materials in a very chemoselective
manner while creating very efficiently a large number of new
bonds and stereogenic centers.
Based on our preceding studies on the enantioselective
Michael addition of b-ketoamides to a,b-unsaturated carbon-
yl derivatives,[15] we started our investigations by mixing the
N-tosyl-b-ketoamide 1a, 2-aminophenol (2a), and acrolein
(3) in the presence of bifunctional Takemoto catalyst (R,R)-4
and crushed 4 ꢀ molecular sieves in dry toluene at room
temperature (Table 1, entry 1). Pleasingly, the expected
DABCO 5a was formed as the only product and isolated in
74% yield with 14:1 d.r. and an encouraging 87:13 e.r. X-ray
diffraction analyses of the product allowed the determination
[*] Dr. M. M. Sanchez Duque, Dr. O. Baslꢀ, Dr. X. Bugaut,
Prof. Dr. T. Constantieux, Prof. Dr. J. Rodriguez
Aix Marseille Universitꢀ, Centrale Marseille, CNRS,
iSm2 UMR 7313, 13397, Marseille (France)
E-mail: xavier.bugaut@univ-amu.fr
Dr. Y. Gꢀnisson, Dr. J.-C. Plaquevent
Universitꢀ Paul Sabatier Toulouse III, CNRS, LSPCMIB UMR 5068
31062 Toulouse (France)
[**] We warmly thank Dr. N. Vanthuyne and M. Jean for HPLC analyses
on a chiral stationary phase, Dr. M. Giorgi for X-ray diffraction
analyses, and the whole team of the Spectropole (http://www.
edged for the preparation of some starting materials. Financial
support from Aix Marseille Universitꢀ, the CNRS, the ANR (project
CIL-MCRs, ANR-07-CP2D-06), and the COST action CM0905 ORCA
is acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 14143 –14146
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14143