Asymmetric organocatalytic domino Michael/aldol reactions: Enantioselective synthesis of chiral cycloheptanones, tetrahydrochromenones, and polyfunctionalized bicyclo-[3.2.1]octanes

Full text of DOI:10.1002/anie.200900754

Angewandte
Chemie
DOI: 10.1002/anie.200900754
Asymmetric Domino Catalysis
Asymmetric Organocatalytic Domino Michael/Aldol Reactions:
Enantioselective Synthesis of Chiral Cycloheptanones,
Tetrahydrochromenones, and Polyfunctionalized Bicyclo-
[3.2.1]octanes**
Magnus Rueping,* Alexander Kuenkel, Francisco Tato, and Jan W. Bats
Dedicated to Professor Joachim W. Engels on the occasion of his 65th birthday
In organic synthesis the use of various carbonyl compounds is
commonplace as they enable diverse C-C coupling reactions.
The use of 1,2-diones is not as widespread and their reactivity
has hardly been examined despite their functionality, which
offers a useful starting point for additional transformations.
Therefore, 1,2-diones represent a group of interesting syn-
thetic building blocks for future study.[1]
Following our recently reported development of an
organocatalytic asymmetric addition/cyclization cascade
using different 1,3-diketones [Eq. (1)],[2] and given the
interesting synthetic possibilities provided by the 1,2-
diones,[3] we decided to examine a Lewis base catalyzed
reaction of a,b-unsaturated aldehydes with 1,2-diones.
showed that the use of catalytic amounts of a secondary amine
enabled a reaction which resulted in the formation of the
bicyclic compound 3a. Accordingly, and in contrast to the
addition/cyclization reaction that we observed in our previous
work with 1,3-diketones, it was concluded that a domino
Michael/aldol reaction occurred by iminium/enamine activa-
tion.[5]
On the basis of these observations we decided to develop
an asymmetric version of this domino reaction.[6–8] The
diarylprolinol ethers 4a–d were used as chiral catalysts in
the reaction of 1a with cinnamylaldehyde (2a). Remarkably,
the bicyclo[3.2.1]octane-6-carbaldehyde derivative 3a was
obtained exclusively as a single diastereomer, demonstrating
the stereocontrol of four stereogenic centers, in good yields
and with excellent enantioselectivities (Table 1, entries 1–3).
The sterically demanding catalysts 4b and 4c (Table 1,
entries 2 and 3) exhibited longer reaction times than the
diphenylprolinol ether 4a, which also delivered better
enantioselectivities and yields (Table 1, entry 1). The unpro-
tected diphenylprolinol 4d also gave good selectivities,
however, with reduced reactivity, possibly indicating aminal
formation of the activated iminium ion (Table 1, entry 4).[9]
To optimize the reaction, we examined the use of different
solvents. The new asymmetric domino Michael/aldol reaction
was carried out in various solvents without notable differ-
ences in stereocontrol (Table 1, entries 5–9). Product 3a was
not formed when tetrahydrofuran (THF) or DMSO (di-
methylsulfoxide) were used (Table 1, entries 10 and 11). We
chose ethanol as a solvent because of the short reaction time
and the better course of the reaction. Experiments run at low
temperatures showed similar results to those conducted at
room temperature; however, longer reaction times were
required.
In planning our investigation of the reaction, the question
arose as to whether the reaction of a dione with an aldehyde is
indeed analogous to our previously described Michael
addition/cyclization reaction which would result in the
corresponding acetals [Eq. (2), path a] or whether, after the
Michael addition an intramolecular aldol reaction would
occur, leading to highly substituted cyclopentanones [Eq. (2),
path b].[4]
We began our investigation by examining the Lewis base
catalyzed reaction of 1,2-cyclohexadione (1a) with the a,b-
unsaturated aldehyde 2a. Indeed, the initial experiments
[*] Prof. Dr. M. Rueping, Dipl.-Chem. A. Kuenkel, Dr. F. Tato
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax: (+49)241-809-2127
E-mail: magnus.rueping@rwth-aachen.de
Dr. J. W. Bats
Institute of Organic Chemistry and Chemical Biology
University Frankfurt, Frankfurt am Main (Deutschland)
[**] The authors acknowledge Evonik Degussa and the DFG (Priority
Programme Organocatalysis) for financial support as well the Fonds
der Chemischen Industrie for a stipend given to A.K.
Under the optimized reaction conditions, the substrate
scope of the domino Michael/aldol reaction was examined by
Supporting information for this article is available on the WWW
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Table 1: Catalyst and solvent investigations of the enantioselective
domino Michael/aldol reaction.[a]
synthesis of a diverse collection of bicyclo[3.2.1]octane-6-
carbaldehydes in good yields and with excellent enantiose-
lectivities (90–98% ee).
The highly functionalized products 3 can be used in a
variety of additional transformations. Of particular interest,
are the multisubstituted chiral cycloheptanones which form
the core structure of many natural products and biologically
active molecules, and are not generally accessible. By using
sodium borohydride in ethanol we reduced both carbonyl
groups of 3a to the corresponding alcohols, and subsequent
oxidative cleavage using sodium periodate[10] provided the
trisubstituted seven-membered ring 5 without loss in the
enantiomeric excess (Scheme 1).
Entry[b]
Solvent
t [h]
Cat.
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
toluene
Et2O
CH2Cl2
CHCl3
MeCN
THF
7
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4a
77
66
75
53
76
76
73
74
46
–
96
92
94
81
96
96
95
97
93
–
24
24
24
24
24
24
24
40
72
72
9
10
11
DMSO
–
–
[a] TMS=trimethylsilyl. [b] Reaction conditions: 0.2m solution of 1,2-
cyclohexadione (1a; 1.2 equiv), aldehyde 2a (1 equiv), and 4 (10 mol%)
at RT. [c] Yield of the product isolated after chromatography. [d] Deter-
mined by HPLC analysis.
Scheme 1. The synthesis of the polysubstituted cycloheptanone 5 from
the domino Michael/aldol product 3a.
Furthermore, the bicycle 3a can be elegantly transformed
into compound 6 (Scheme 2), which in principle, could have
occurred through the addition/cyclization reaction [Eq. (2a)].
The base-induced retro-aldol reaction[11] led to the opening of
the diketone which was then cyclized to the hemiacetal 6; this
reaction sequence is the first example of such a retro-aldol/
cyclization reaction.
using various a,b-unsaturated aldehydes 2 (Table 2). Aro-
matic a,b-unsaturated aldehydes having both electron-with-
drawing (Table 2, entries 2, 6, and 7) and electron-donating
substituents (Table 2, entries 3–5) can effectively be used in
this transformation; the substitution pattern of the arene had
no influence on the enantioselectivity of the reaction (Table 2,
entris 2–7). Additionally, it was possible to use both hetero-
aromatic (Table 2, entries 8 and 9) and aliphathic aldehydes
(Table 2, entry 10) in this reaction. The ability to control the
formation of four new stereogenic centers permitted the
Table 2: Substrate scope of the new Michael/aldol reaction.
Scheme 2. Retro-aldol cyclization reaction.
In addition to the double reduction of the aldehyde and
ketone using sodium borohydride, the aldehyde group of
compound 3a can also be reduced selectively to the alcohol
with triethylsilane and boron trifluoride etherate. Hereby, we
were able to isolate diol 7 and triol 8 while maintaining the
stereochemistry (Scheme 3). In the reduction that gave
Entry[a]
Product
R
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
Ph
77
79
80
62
66
60
68
81
77
44
96
95
95
96
98
93
96
95
90
98
4-MeOC6H4
4-BrC6H4
3-BrC6H4
2-NO2C6H4
4-N(Me)2C6H4
benzo[1,3]dioxol-5-yl
2-furanyl
2-thiophenyl
n-butyl
3e
3 f[d]
3g
3h[e]
3i[e]
3j[e,f]
10
[a] Reaction conditions: 0.2m ethanol solution, 1,2-cyclohexadione (1a;
1.2 equiv), aldehyde 2 (1 equiv), and 4a (10 mol%) at RT. [b] Yield of the
product isolated after chromatography. [c] Determined by HPLC analysis.
[d] 20 mol% 4a used at RT. [e] Reduced aldehyde was used for the
determination of enantiomeric excess. [f] 20 mol% 4a used at 08C, 72 h.
Scheme 3. Single and double reduction of the bicycle 3a.
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compound 8 an additional stereocenter is stereoselectively
formed, which is controlled by the conformation of adduct 3a.
The crystal structure of 8 shows that the nucleophilic attack
occurs from the Re face of 3a (Figure 1).[12] To determine the
In summary, we have developed a new diastereo- and
enantioselective Lewis base catalyzed domino Michael/aldol
reaction in which the formation of four stereogenic centers is
controlled. Several a,b-unsaturated aldehydes can be used to
provide access to chiral bicyclo[3.2.1]octane-6-carbaldehydes
in good yields and with excellent enantioselectivities (90–
98% ee). In addition, we described the targeted synthesis of
bicyclic diols and triols, as well as introduced a new retro-
aldol/cyclization reaction which enables easy access to
valuable tetrahydrochromenones. Finally, our newly devel-
oped organocatalytic domino reaction allows the synthesis of
chiral polysubstituted seven-membered rings that are gener-
ally difficult to synthetically access and which can be used in
the future synthesis of natural products.
Received: February 7, 2009
Published online: April 17, 2009
Keywords: aldol reaction · domino reaction · Michael addition ·
.
organocatalysis · prolinol ethers
Figure 1. Molecular structure of the bicyclic triol 8 (right) and ester of
7 (left). The thermal ellipsoids are shown at the 50% probability level.
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