A highly enantioselective Bronsted acid catalyzed reaction cascade

Article abstract of DOI:10.1002/anie.200801435

(Chemical Equation Presented) One cat. is enough! A highly enantiose-lective reaction has been developed for the three-component reaction of an enamine with a vinyl ketone and a Hantszsch ester in which each of the six reaction steps is catalyzed by the same chiral Bronsted acid (see scheme). This reaction offers efficient access to tetrahydropyridines and azadecalinones from simple and readily available starting materials.

Full text of DOI:10.1002/anie.200801435

Communications
DOI: 10.1002/anie.200801435
Asymmetric Catalysis
A Highly Enantioselective Brønsted Acid Catalyzed Reaction
Cascade**
Magnus Rueping* and Andrey P. Antonchick
Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 75th birthday
Enantioselective domino reactions have emerged as powerful
methods for the rapid synthesis and construction of complex
target molecules starting from simple and readily available
precursors.[1] Asymmetric organocatalytic cascade reactions
represent an important and promising area in organic syn-
thesis, providing direct access to enantioenriched compounds
under mild and environmentally friendly reaction conditions.
Generally these organocascades are based on biomimetic
principles, and often aminocatalytic activation is the key for
successful execution.[2]
Over the past few years Brønsted acid catalysts, including
chiral phosphoric acids,[3] have been applied in asymmetric
synthesis, whereby the chiral phosphate counterion formed as
a intermediate induces high enantioselectivities. As part of
our studies we have recently demonstrated that chiral
Brønsted acids can serve as powerful catalysts for the
enantioselective activation of imines[4] and carbonyl function-
alities.[5] Here we report a new asymmetric organocatalytic
cascade reaction in which multiple steps are catalyzed by a
chiral Brønsted acid catalyst and which provides valuable
tetrahydropyridines[6] and azadecalinones[7] with high enan-
tioselectivities [Eq. (1)].
corydendramine, leptophylline, morusimine, and juliproso-
pine.[7–9]
We have previously demonstrated that chiral 1,1’-bi-2-
naphthyl (binol) phosphates are excellent catalysts for the
enantioselective metal-free reduction of imines, quinolines as
well as pyridines. Based on our original biomimetic strategy
and our experience in chiral ion-pair catalysis, we envisioned
a new organocatalytic multiple-reaction cascade sequence
comprising a Michael addition, isomerization, cyclization,
elimination, isomerization, and transferhydrogenation in
which each single step is catalyzed by a chiral Brønsted acid
(Scheme 1).
Chiral azadecalinones are important starting materials for
numerous biologically active molecules, such as the alkaloids
pumiliotoxin and gephyrotoxin, as well for over 200 2,5-
disubstituted decahydroquinolines. Whereas the tetrahydro-
pyridines are precursors for the synthesis of 2,6-dialkyl-
substituted 3-hydroxypiperidines such as cassin, spectaline,
Scheme 1. Brønsted acid catalyzed multiple-reaction cascade.
In our reaction design we assumed that exposure of a
mixture of enamine 1 and a,b-unsaturated ketone 2 to
catalytic amounts of the Brønsted acid should lead to
formation of the corresponding 1,4-addition products[5b] 4a
and 4b. Subsequent Brønsted acid catalyzed cyclization of 4a,
which is in an acid-catalyzed equilibrium with 4b, would give
the hemiaminal 5, which upon rapid elimination of water
results in the formation the dihydropyridine 6, an intermedi-
ate also observed in the enantioselective reduction of
pyridine.[2l] The following Brønsted acid catalyzed protona-
tion should effect the generation of an iminium ion, the chiral
ion pair 7, which is activated for an enantioselective hydride
transfer[10] to give the desired product 9.[11] Central to the
[*] Prof. Dr. M. Rueping, Dr. A. P. Antonchick
Degussa Endowed Professorship
Institute for Organic Chemistry and Chemical Biology
Johann Wolfgang Goethe-University Frankfurt am Main
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
E-mail: M.rueping@chemie.uni-frankfurt.de
[**] The authors acknowledge Evonik Degussa and the DFG (Priority
Programme Organocatalysis) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801435.
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Angewandte
Chemie
Table 1: Scope of the enantioselective Brønsted acid catalyzed cascade
reaction.[a]
utility of this new multiple reaction cascade in asymmetric
synthesis is the requirement that the last Brønsted acid
catalyzed activation step in this sequence would proceed with
high enantiocontrol.
9a
9b
10b
10c
Preliminary studies revealed that the proposed new
Brønsted acid catalyzed cascade could indeed be performed
and that the three-component reaction of enamine 1, vinyl
ketone 2, and dihydropyridine 8 results in the corresponding
products 9/10 when, for instance, phosphates are employed as
catalysts. The subsequent survey of different chiral phos-
phates revealed that binol phosphates with large aromatic
substituents in 3,3-position of the binaphthyl backbone
provided good enantioselectivities, and the best results were
obtained with catalyst 3 (aryl = 9-anthracenyl; Scheme 2).
9c
9d
10d
10e
9e
9 f
9g
10 f
10g
10h
Scheme 2. Brønsted acid catalyzed enantioselective multiple-reaction
cascade for the synthesis of tetrahydropyridines.
In further optimization we focused on varying the reaction
parameters including solvent, concentration, temperature,
catalyst loading, and hydride source. In these experiments the
best results with regard to reactivity and selectivity were
obtained when the reaction cascade was performed at
elevated temperatures in aromatic or halogenated solvents.
Using the optimal reaction conditions we investigated the
scope of the new Brønsted acid catalyzed reaction cascade
(Table 1). In general different enamines 1 as well as vinyl
ketones 2 could be applied successfully in this multiple-
reaction cascade, providing a diverse set of tetrahydropyr-
idines[7] 9a–g and azadecalinones[8] 10a–i with different
aromatic and aliphatic substitutents in good yields and with
excellent enantioselectivities (89–99% ee). The constitution
and absolute configuration of the new products was proven by
X-ray crystal structure analysis as we were able to obtain
suitable single crystals of tetrahydropyridine 9b (Figure 1).
In summary, we have developed a new highly enantiose-
lective Brønsted acid catalyzed multiple-reaction cascade
10a
10i
[a] Reactions were performed with enamine 1, vinyl ketone 2 (1.2 equiv),
Hantzsch ester 8 (1.1 equiv), and catalyst 3 (5 mol%) at 508C in
chloroform or benzene [b] Yields were determined after column
chromatography. [c] Determined by HPLC on using a stationary phase.
[d] Ketone (2 equiv) and Hantzsch ester (2 equiv).
based on a biochemical blueprint. In this new three-compo-
nent reaction each step of the six-step sequence is catalyzed
by the same chiral Brønsted acid allowing rapid, direct, and
efficient access to valuable tetrahydropyridines and azadeca-
linones from simple readily available starting materials with
the highest levels of enantiocontrol (Table 1). The work
described here demonstrates that a single chiral Brønsted acid
catalyst can facilitate a series of different reaction steps to
construct complex molecular structures in a highly stereose-
lective fashion; this again proves chiral Brønsted acids to be
powerful and effective tools for organic synthesis.
Received: March 26, 2008
Figure 1. Molecular structure of tetrahydropyridine 9b.
Published online: June 24, 2008
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5837

Communications
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Keywords: Michael reaction · organocatalysis · phosphates ·
piperidines · reductive amination
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