Asymmetric Michael reaction of acetaldehyde catalyzed by diphenylprolinol silyl ether

Article abstract of DOI:10.1002/anie.200801130

(Chemical Equation Presented) An acetaldehyde breakthrough: The catalytic asymmetric Michael addition reaction of acetaldehyde and various nitroalkenes in the presence of a chiral diphenylprolinol silyl ether organocatalyst is described (see scheme; TMS =

Full text of DOI:10.1002/anie.200801130

Communications
DOI: 10.1002/anie.200801130
Organocatalysis
Asymmetric Michael Reaction of Acetaldehyde Catalyzed by
Diphenylprolinol Silyl Ether**
Yujiro Hayashi,* Takahiko Itoh, Masahiro Ohkubo, and Hayato Ishikawa
Table 1: The effect of the catalyst and the solvent on the Michael reaction
of acetaldehyde and nitrostyrene.[a]
Reactions involving organocatalysis have developed rapidly
in recent years.[1] Although many kinds of enantioselective
reactions of aldehydes involving the enamine-type mecha-
nism[2] have been developed, there has been no report of the
successful use of acetaldehyde, despite its usefulness, in
catalytic asymmetric reactions.[3] Control of the reactivity of
acetaldehyde is difficult because of its high reactivity as both a
nucleophile and an electrophile. Moreover, the addition
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
proline
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
hexane
toluene
H2O
THF
<10
75
<10
<10
<10
53
47
13
53
1
2
3
4
1
1
1
1
96
product possesses
a reactive a-unsubstituted aldehyde
moiety that can potentially react with a nucleophile or an
electrophile to give several side products. Recently, however,
our group[4] and the group of List[5] independently developed
the first enantioselective catalytic reactions of acetaldehyde.
We reported a crossed-aldol reaction of acetaldehyde cata-
lyzed by diarylprolinol, and List and co-workers reported the
proline-catalyzed Mannich reaction of acetaldehyde.
The Michael reaction, a synthetically important carbon–
carbon bond-forming reaction, is catalyzed enantioselectively
by organocatalysts.[6] However, despite the many successful
Michael reactions, in which aldehydes act as nucleophiles,[7]
we are not aware of any report of a Michael reaction using
acetaldehyde. Previously, we developed Michael reactions of
aldehydes and nitroalkenes catalyzed by diphenylprolinol
silyl ether[8] to afford a-substituted g-nitro aldehydes in nearly
optically pure form. The Michael adduct that is generated is
synthetically useful; Enders and co-workers developed an
elegant domino reaction based on the Michael reaction to
generate chiral cyclohexene derivatives with excellent enan-
tioselectivities.[9] In these previous Michael reactions, only a-
substituted aldehyde derivatives were synthesized, but it is
desirable to prepare chiral a-unsubstituted g-nitro aldehydes
with excellent enantioselectivity. Herein, we describe the first
example of such a reaction.
95
93
92
95
[a] Unless otherwise shown, the reaction was performed with nitro-
styrene (0.75 mmol), acetaldehyde (7.5 mmol), catalyst (0.075 mmol),
and solvent (150 mL) at room temperature for 18 h. [b] Yield of isolated
product. [c] Optical purity was determined by chiral GCanalysis. See the
Supporting Information for details.
(Figure 1), which afforded good results in the Mannich
reaction[5] and the aldol reaction[4] of acetaldehyde, respec-
tively. Although diphenylprolinol 2 did not promote the
The Michael reaction of nitrostyrene and acetaldehyde
was selected as a model reaction (Table 1). Organocatalysts
were examined first and the results are summarized in
Table 1. A reaction did not occur in the presence of either
Figure 1. Organocatalysts examined in this study. TMS=trimethylsilyl.
proline or trifluoromethyl-substituted diarylprolinol
4
reaction, silyl ether 1, which was developed by our group,[8,10]
was effective and provided the Michael product in good yield
with excellent enantioselectivity. Notably, the reactivity of
diphenylprolinol silyl ether 1[11] and that of trifluoromethyl-
substituted diarylprolinol silyl ether 3,[11] which is an effective
organocatalyst in several asymmetric reactions developed by
Jørgensen and co-workers,[12] are very different in the present
reaction. After screening solvents, 1,4-dioxane was found to
afford the best results.
[*] Prof. Dr. Y. Hayashi, T. Itoh, M. Ohkubo, Dr. H. Ishikawa
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
After the reaction conditions were optimized the general-
ity of the reaction was investigated, and the results summar-
ized in Table 2 show that the reaction has broad applicability.
Nitroalkenes with either phenyl or naphthyl substituents
[**] This work was partially supported by the Toray Science Foundation
and a Grant-in-Aid for Scientific Research from MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
(Table 2, entry 2) gave excellent results. Aryl-substituted
nitroalkenes, having both electron-rich and electron-deficient
aryl groups, successfully afforded the Michael adducts in high
yield with excellent enantioselectivity (Table 2, entries 3–7).
Heteroaryl-substituted nitroalkenes were also suitable sub-
strates (Table 2, entry 8). The reaction proceeded not only
with aryl-substituted nitroalkenes, but also with alkyl-sub-
stituted nitroalkenes to give nearly optically pure Michael
adducts (Table 2, entries 9 and 10).
The Michael addition products are important chiral
intermediates that possess synthetically useful functional
groups such as formyl and nitro groups. For instance, we
have already established synthetic routes for baclofen,[13]
a
therapeutically useful GABAB receptor agonist, and prega-
balin,[14] an important anticonvulsant drug, from 5e and ent-
5j, respectively.[15] Whereas the enantiomeric excess of ent-5j
in our previous synthesis was 91%,[15] that obtained by using
the present method is over 99%, highlighting one of the
superior features of the present Michael reaction.
In the crossed-aldol reaction of acetaldehyde, trifluoro-
methyl-substituted diarylprolinol is the effective catalyst, and
hydrogen-bond interactions between the formyl oxygen atom
and the hydroxy group of the catalyst may control the
transition state. In the present Michael reaction, diphenyl-
prolinol silyl ether is an efficient
Table 2: Catalytic asymmetric Michael reaction of acetaldehyde with
various nitroalkenes.[a]
Entry
1
Product
t [h]
Yield [%][b]
75
ee [%][c]
catalyst, but similar hydrogen-bond-
ing interactions are not expected to
occur. The reaction may proceed by
the same transition state proposed for
5a
5b
18
96
the reaction of propanal and nitro-
alkene catalyzed by the same catalyst
(Figure 2):[8] The selectively gener-
2
28
70
92
Figure 2. The transition-
ated anti enamine may react with state model.
the nitroalkene by Seebachꢀs acyclic
synclinal transition-state model.[16] It
is remarkable that excellent enantioselectivity has been
realized, even though a small enamine without a b substituent
has been employed.
3
4
5
6
5c
5d
5e
5 f
27
18
36
42
69
73
75
72
94
93
92
95
In summary, we have developed the first asymmetric
Michael reaction of acetaldehyde to afford a-unsubstituted g-
nitro aldehyde in good yield with excellent enantioselectivity.
The resulting product possesses useful functional groups, such
as nitro and formyl groups, that make them synthetically
important chiral building blocks. The present reaction also
indicates that the enantiofacial selection of the enamine
derived from acetaldehyde can be realized by the combina-
tion of acetaldehyde and diphenylprolinol silyl ether. This
new finding will have broad application in synthetic organic
chemistry.
7
8
5g
5h
24
48
77
72
93
97
Experimental Section
Typical procedure: Acetaldehyde (420 mL, 7.5 mmol) was added to a
mixture of (S)-diphenyltrimethylsiloxymethyl pyrrolidine (24.4 mg,
0.075 mmol) and nitrostyrene (111.8 mg, 0.75 mmol) in 1,4-dioxane
(0.15 mL) in a sealed tube (ACE GLASS, product number 5027-05) at
48C. The reaction mixture was stirred at room temperature for 18 h
and then quenched with aq. 1n-HCl. The organic materials were
extracted three times with ethyl acetate. The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. Purification by column chromatography (ethyl
9
5i
5j
36
72
54
61
99
10
>99
acetate/hexane = 1:20!1:6)
gave
(S)-4-nitro-3-phenylbutanal
[a] Unless otherwise shown, the reaction was performed with nitroalkene
(0.75 mmol), acetaldehyde (7.5 mmol), catalyst 1 (0.075 mmol), and 1,4-
dioxane (150 mL) at room temperature. [b] Yield of isolated product.
[c] Optical purity was determined by chiral HPLCanalysis after
conversion of the aldehyde into the corresponding alcohol by reduction
with NaBH4 or chiral GCanalysis. See the SI for details.
(108.1 mg, 0.56 mmol) in 75% yield. The enantiometric excess was
determined to be 96%.
Received: March 8, 2008
Published online: April 25, 2008
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www.angewandte.org
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Communications
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Keywords: acetaldehyde · asymmetric catalysis ·
Michael addition · synthetic methods
.
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