Catalytic asymmetric domino Michael-Henry reaction: Enantioselective access to bicycles with consecutive quaternary ceuters by using bifunctional catalysts

Article abstract of DOI:10.1002/chem.201000237

Chemical Equotion Presentation Domino catalysis: Two consecutive quaternary stereocenters, three functional groups, and four stereogenic centers have been created in the newly developed domino Michael-Henry reaction (see scheme) employing small amounts of a bifunctional organocatalyst.

Full text of DOI:10.1002/chem.201000237

COMMUNICATION
DOI: 10.1002/chem.201000237
Catalytic Asymmetric Domino Michael–Henry Reaction: Enantioselective
Access to Bicycles with Consecutive Quaternary Centers by Using
Bifunctional Catalysts
Magnus Rueping,*[a] Alexander Kuenkel,[a] and Roland Frçhlich[b]
The use of domino and cascade reactions provides a pow-
erful tool in organic synthetic chemistry. The possibility of
forming several bonds in one step without isolating the in-
termediates, changing the reaction conditions, or adding re-
agents reduces the production costs and simplifies process-
es.[1] Performing these reactions, for instance, in the presence
of chiral organocatalyst complex structures can be obtained
with high stereoselectivities.[2] In line with our latest studies
towards the development of different asymmetric cascade
and domino reactions using organocatalysts, such as chiral
Brønsted acids[3] and prolinol derivatives,[4] we became inter-
ested in exploring a new enantioselective domino reaction
of 1,2-diones with nitroalkenes which would lead to unpre-
cedented polyfunctionalized bicycles. We assumed that the
1,2-diones would undergo a Michael addition to the nitroal-
kenes, followed by an intramolecular Henry reaction[5] to
afford multifunctionalized bicycles containing four stereo-
genic centers of which two can be neighboring quaternary
centers [Eq. (1)].
Initially we proposed a Brønsted base catalyzed activation
of the 1,2-dione which would result in the formation of the
enolic tautomer of the dione and thus the nucleophilicity of
this substrate should be enhanced. Therefore, we started our
experimental investigations by reacting cyclohexa-1,2-dione
7 with the b-nitrostyrene (8a), employing catalytic amounts
of the achiral base 1,4-diazabicyclo
These experiments revealed that base-catalyzed transforma-
tions could be achieved and that the bicyclo[3.2.1]octan-8-
ACHTUNGERTN[NUNG 2.2.2]octane (DABCO).
AHCTUNGTRENNUNG
one (9a) can be isolated in good yields. Based on these ob-
servations, we decided to develop an asymmetric version of
this unprecedented domino reaction.
Several chiral organocatalysts were used to study the
enantioselective domino Michael–Henry reaction (Figure 1).
Based on the successful application of DABCO as an achiral
catalyst, we investigated cinchonine 1 as a chiral Brønsted
base catalyst[6] and we were able to isolate the product 9a
with moderate enantioselectivities (Table 1, entry 1).
In subsequent investigations, we applied cupreidine (2)[7]
and trimethylsilyl O-protected cinchonine 3 as catalysts in
the domino reaction. Interestingly, we isolated only a race-
mic mixture of product 9a (Table 1, entry 2 and 3). These
experiments indicated that the asymmetric version of the
domino reaction is not controlled by Brønsted base catalysis.
[a] Prof. Dr. M. Rueping, Dipl.-Chem. A. Kuenkel
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-8092665
E-mail: magnus.rueping@rwth-aachen.de
[b] Dr. R. Frçhlich
Organisch Chemisches Institut, University Mꢀnster
Correnstrasse 40, 48149 Mꢀnster (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000237.
Figure 1. Brønsted base and bifunctional chiral organocatalysts.
Chem. Eur. J. 2010, 16, 4173 – 4176
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4173

It appeared that the 1,2-aminoalcohol moiety of the cincho-
nine 1 plays a crucial role in the enantiocontrol of this reac-
tion and acts as a bifunctional organocatalyst. Surprisingly,
even the use of commercially available ephedrine (4) result-
ed in the formation of bicycle 9a with moderate enantiose-
lectivity (Table 1, entry 4). These results again emphasize
the importance of the bifunctionality of the catalyst used in
the asymmetric version of this new domino Michael–Henry
reaction.
cally favored diastereomer is produced (Table 2, entry 5).
From these experiments it also becomes apparent that the
reaction time has an impact on the diastereomeric ratio; the
longer the reaction time the lower the diastereomeric ratio
(Table 1, entry 6 and Table 2, entry 1). This indicates a base-
catalyzed isomerization.
Table 2. Influence of catalyst loading, 1,2-dione amount and temperature
on the enantioselective domino Michael–Henry reaction.
Table 1. Evaluation of different bifunctional chiral organocatalysts.
Entry[a] mol% cat. T [8C] 7 [equiv] Yield [%][b] d.r.[c] ee [%][d]
1[e]
2
3
4
5
10
1
1
0.5
1
RT
RT
RT
RT
50
1.2
1.2
1.0
1.0
1.0
94
84
58
44
63
1.7:1 93, 94
1:3.3 92, 94
1:5.5 93, 98
1:7.7 91, 98
1.2:1 91, 98
Entry[a]
Catalyst
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
1
2
3
4
5
6
3
1.5
24
6
<1
<1
85
86
80
82
92
91
3:1
9:1
8.3:1
5:1
2:1
3:1
45, 24
rac/rac
rac/rac
À36, À30
À83, À89
87, 92
[a] Reaction conditions: 0.2m toluene solution, 1,2-cyclohexadione 7, 8a
(1.0 equiv), catalyst 6. All reactions were stopped after 24 h.[b] Yield of
isolated product after column chromatography. [c] Determined by
1H NMR spectroscopy. [d] Enantiomeric excess was determined by
HPLC.[e] This reaction was completed in less than 15 min.
[a] Reaction conditions: 0.2m toluene solution, 1,2-cyclohexadione
7
(2.0 equiv), 8a (1.0 equiv), 10 mol% catalyst at RT. [b] Yield of isolated
product after column chromatography. [c] Determined by 1H NMR spec-
troscopy. [d] Enantiomeric excess was determined by HPLC.
Having established the optimal reaction conditions, we
decided to explore the scope of this newly developed asym-
metric domino Michael–Henry reaction yielding bicycles
with four stereocenters in a one-pot reaction sequence
(Table 3). In general, various b-nitroalkenes with different
substitution patterns, having both electron-donating
(Table 3, entry 2–5) and electron-withdrawing groups
(Table 3, entry 6–9), can be used in this transformation to
obtain the corresponding products in good yields and with
excellent enantioselectivities throughout. Additionally, for
the first time it was possible to use b-disubstituted nitro-
With this knowledge in hand, we substituted the alcohol
group of cinchonine 1 by a thiourea moiety to obtain cata-
lyst 5[8] with enhanced hydrogen-bond-donor capacity.[9,10]
Application of this catalyst 5 resulted in the opposite enan-
tiomer with better enantioselectivities (Table 1, entry 5). In
addition to the impact the thiourea residue has on enantio-
selectivity, the results show that the absolute configuration
of the cinchonine derivative in the 9-position determines the
stereochemical outcome of the reaction (Figure 1 and
Table 1). Underlining this concept, the cinchonidine-based
thiourea catalyst 6, the pseudoenantiomer of 5, affords the
opposite enantiomer with excellent enantioselectivities
(Table 1, entry 6).
For further optimization, the substrate concentration, as
well as catalyst loading, was varied (Table 2). These experi-
ments revealed that the best results with regard to reactivity
and selectivity were obtained with 1.0 mol% catalyst
(Table 2, entry 2). In varying substrate concentration, the se-
lectivity can be improved by decreasing the amount of 7 to
1.2 equivalents (Table 2, entry 1). The lower substrate con-
centration of the nucleophile 7 causes statistically less
Brønsted base activation and thus, an increase of bifunction-
al substrate activation is observed, which is fundamental for
obtaining high enantioselectivities. Further reduction of the
catalyst loading to 0.5 mol% also resulted in excellent enan-
tioselectivities; however, lower yields were observed and the
diastereomeric ratio was reversed. The latter observation in-
dicates a base-catalyzed epimerization at the a-nitro posi-
tion of the product 9a. This is also observed if the reaction
is performed at 508C where again more the thermodynami-
AHCTUNGTREGsNNUN tyrenes, which lead to the bicycles 9j and 9k with two
neighboring quaternary stereocenters (Table 3, entry 10 and
11). Interestingly, the products 9j and 9k could be isolated
almost as a single diastereomer and with excellent enantio-
selectivities.
The molecular structure of 9k was determined by X-ray
crystal-structure analysis and revealed that the kinetically
favored product is the major diastereoisomer in which the
aryl moiety and the nitro group have a syn-configuration
(Figure 2).
Mechanistically we propose that the Michael–Henry
domino reaction is catalyzed by a bifunctional thiourea cin-
chonidine involving a hydrogen-bond and base-catalyzed ac-
tivation of the nitrostyrene and 1,2-dione, respectively. With
regard to the base-induced epimerization of the products
our experimental results indicate that two possible pathways
exist, a slow and a fast one (Scheme 1).
The fast pathway is a deprotonation–reprotonation of the
a-nitrocarbon atom due to the lower basicity as compared
to the alcohol, yielding the thermodynamically favored dia-
stereoisomer.
4174
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Chem. Eur. J. 2010, 16, 4173 – 4176

Asymmetric Domino Michael–Henry Reaction
COMMUNICATION
Table 3. Substrate scope of the bifunctional catalyzed domino Michael–
Henry reaction.
a proton at the a-nitrocarbon. Due to the higher diastereo-
meric ratio of 9j and 9k, this pathway must be slower
(Table 3, entry 10 and 11).
In summary, for the first time we are able to report the
development of a bifunctional cinchona-based, thiourea-cat-
alyzed, enantioselective domino reaction of cyclohexa-1,2-
dione with variously substituted b-nitrostyrenes, which pro-
Entry[a] Product R1
R2
Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9 f
9g
9h
9i
Ph
H
H
H
H
H
H
H
H
H
84
70
73
75
87
74
81
73
83
1:3.3 92, 94
vides complex, polyfunctionalized bicycloACTHNGUETRNNU[G 3.2.1]octan-8-ones.
p-MePh
o-MeOPh
m-MeOPh
p-MeOPh
p-FPh
1:2
92, 97
In this efficient domino Michael–Henry reaction diverse b-
nitrostyrenes can be successfully applied and the bicyclic
products, containing four stereogenic centers of which two
may be neighboring quaternary stereocenters, can be isolat-
ed in good yields with excellent enantioselectivities (91–
97% ee). Furthermore, we demonstrate the significance of a
bifunctional activation mode compared to a base-catalyzed
activation in order to gain high enantiocontrol. With regard
to the mechanism, we reveal a base-induced epimerization
in this unprecedented domino reaction, which provides the
opportunity to control the predominant formation of one of
the diastereomers. It is notable that this can be achieved by
using just 0.5–1.0 mol% catalyst, allowing low cost, ready
access to complex enantiopure compounds that can be ap-
plied as valuable chiral building blocks in synthetic organic
and medicinal chemistry.
1:3.3 91, 92
1:1.3 96, 93
1:1.7 94, 97
1:1.2 96, 94
o-FPh
1:2
3:1
10:1
1:33
1:25
93, 95
94, 91
94, 96
92, –
3,4-(Cl)2Ph
m-BrPh
Ph
9
10
11
9j
9k
Me 60
Me 70
p-ClPh
93, –
[a] Reaction conditions: 0.2m toluene solution, 1,2-cyclohexadione
7
(1.2 equiv), 8 (1.0 equiv), 1–2 mol% 6, 3 ꢂ MS at RT. [b] Yield of isolat-
ed product after column chromatography. [c] Determined by 1H NMR
spectroscopy. [d] Enantiomeric excess was determined by HPLC.
Experimental Section
General procedure for the enantioselective domino Michael–Henry reac-
tion: The catalyst 6 (0.5–2 mol%), 1,2-cyclohexanedione (7) (0.28 mmol,
1.2 equiv), b-nitrostyrene (8) (0.24 mmol, 1.0 equiv) and 3 ꢂ molecular
sieve were placed in a screw-capped test tube equipped with a stirring
bar. Toluene (0.2m) was added and the resulting mixture was stirred at
room temperature. Subsequently, the reaction mixture was washed with
saturated NH4Cl solution and extracted with dichloromethane. The com-
bined organic layers were dried over Na2SO4, filtered and evaporated
under vacuum. The crude mixture was purified by column chromatogra-
phy on silica gel (petroleum ether b.p. 40–608C/acetone) to afford the
Figure 2. Molecular structure of the product 9k.
bicycloACTHNUTRGNE[NUG 3.2.1]octan-8-one 9a–j.
Acknowledgements
Scheme 1. Proposed mechanism of the base-catalyzed epimerization of
the product.
We gratefully acknowledge financial support by the DFG (Priority Pro-
gramme Organocatalysis), the European Research Council (ERC
209437) and the FCI for a stipend given to A.K.
Thus, the basicity of the proton at the a-nitrocarbon atom
is determining the base-induced epimerization rate of 9.
Thus, for the chloro- and bromo-substituted bicycles 9h and
9i the thermodynamically favored products are observed
(Table 3, entries 8 and 9). In contrast, the fluorine substitu-
tions in 9 f and 9g do not have a significant impact on the
basicity indicating that the p-effect of the fluorine atoms
must dominate over the electron-withdrawing effect
(Table 3, entry 6 and 7). On the other hand, the deprotona-
tion of the hydroxyl group results in a retro-Henry reaction,
which upon ring closure provides the thermodynamically fa-
vored diastereoisomer. This epimerization has for instance
been observed for products 9j and 9k, which do not contain
Keywords: domino reactions · cascade reactions · hydrogen
bonds · organocatalysis · thioureas
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