Highly enantioselective (S)-homoproline-catalyzed Michael addition reactions of ketones to β-nitrostyrenes

Article abstract of DOI:10.1246/cl.2005.962

Being catalyzed by (S)-homoproline a highly enantioselective organocatalytic Michael addition reaction of ketones to β-nitrostyrenes has been achieved. Copyright

Full text of DOI:10.1246/cl.2005.962

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62
Chemistry Letters Vol.34, No.7 (2005)
Highly Enantioselective (S)-Homoproline-catalyzed Michael Addition Reactions
of Ketones to ꢀ-Nitrostyrenes
Ã
Dai Terakado, Masako Takano, and Takeshi Oriyama
Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received March 25, 2005; CL-050404)
Being catalyzed by (S)-homoproline a highly enantioselec-
tive organocatalytic Michael addition reaction of ketones to
Table 1. (S)-Homoproline-catalyzed asymmetric Michael addi-
a
tion in various solvents
ꢀ
-nitrostyrenes has been achieved.
20 mol%
20 mol%
CO H
• HCl
H
2
/ Et N
N
3
O
O
Ph
The Michael reaction is widely used as one of the most im-
portant carbon–carbon bond-forming reactions in synthetic or-
NO2
+
Ph
NO2
r t / 5 h
1
ganic chemistry. Particularly, the asymmetric Michael reaction
2
b
c
Run
Solvent
Yield /%
ee /%
to nitroalkenes is a very attractive method for the construction
1
2
3
4
5
6
7
8
9
DMSO
DMF
THF
CH2Cl2
CH3CN
MeOH
EtOH
i-PrOH
t-BuOH
t-BuOH
neat
27
33
5
5
7
19
51
49
39
88
11
25
25
32
37
13
32
28
28
37
42
35
of useful chiral building blocks of various natural products, be-
cause the nitro group is easily transformed into an amino group,
nitrile oxide and so on. Recently, L-proline or its derivatives-
catalyzed asymmetric carbon–carbon bond-forming reactions
3
4
such as aldol reaction, the Michael addition, and Mannich-type
5
reaction were studied intensively by many organic chemists.
Excellent enantioselectivity was attained in various types of
organocatalytic asymmetric reactions, but the Michael addition
has some serious limitations. For example, there are scattered
examples over 90% ee, and substrate generality is not so high.
Therefore, the development of a more efficient organocatalytic
and enantioselective Michael reaction was required in asymmet-
ric synthesis.
d
10
11
a
Molar ratio of acetone:nitrostyrene:homoproline:Et3N =
45:1:0.2:0.2. Isolated yield. Determined by HPLC analy-
sis with a chiral column. Reaction was performed for 24 h.
b
c
d
On the other hand, we have recently developed highly effi-
cient organocatalytic asymmetric acylation of a wide variety of
racemic alcohols and meso-diols catalyzed by a chiral 1,2-di-
yield (Run 6). EtOH and i-PrOH promoted the reaction more
efficiently than MeOH and gave the corresponding Michael
adduct in moderate chemical yields (Runs 7 and 8). The highest
enantioselectivity was observed by using t-BuOH in 37% ee
(Run 9). Furthermore, when the reaction time in t-BuOH
became longer (24 h), the corresponding Michael adduct was
obtained in 88% chemical yield and 42% optical yield (Run
10). The reaction in no solvent was not effective (Run 11).
Next, we examined a variety of Michael donors in t-BuOH
(Table 2). The Michael addition of ethyl methyl ketone as a
Michael donor catalyzed by 20 mol % of (S)-homoproline
proceeded with high enantioselectivity compared with acetone
(Run 1). The use of N-methylmorpholine in place of triethyl-
amine gave similar enantioselectivity (Run 2). The best result
in enantioselectivity was obtained using diethyl ketone as a
Michael donor. Diethyl ketone needed longer reaction time
and yielded the desired Michael adduct in 51% chemical yield
with 94% ee which is the best ee among those reported so far
for this substrate (Run 4). 2-Hexanone has lower reactivity
and comparatively high enantioselectivity (Run 5). When cyclo-
hexanone was used, the reaction smoothly proceeded for 20 h,
and yielded the corresponding Michael adduct in 90% chemical
yield with 90% ee (Run 6).
6
amine derived from (S)-proline. And then, we have accomplish-
ed an efficient and practical synthesis of (S)-homoproline, which
is a one-carbon homologated proline, starting from (S)-proline in
7
7
steps. (S)-Homoproline seems to be a potentially interesting
organocatalyst, but no examples using (S)-homoproline itself
in asymmetric synthesis has been reported so far. We envisaged
that (S)-homoproline might catalyze highly enantioselective
carbon–carbon bond formation such as aldol reaction and the
Michael addition. Herein, we wish to report the highly enantio-
selective Michael addition of ketones to ꢀ-nitrostyrenes cata-
lyzed by (S)-homoproline.
Initially, we tried the Michael addition of acetone to trans-
-nitrostyrene under the influence of 20 mol % of (S)-homopro-
ꢀ
line hydrochloride and triethylamine which was added in order
to remove HCl in (S)-homoproline hydrochloride in various
solvents at room temperature for 5 h. The results are summarized
in Table 1. The Michael addition in DMSO gave the desired
8
Michael adduct in 27% chemical yield with 25% optical yield,
and an undesired dinitro adduct was also obtained as a by-
product (Run 1). The use of DMF as a solvent gave comparable
enantioselectivity to DMSO (Run 2). THF and CH2Cl2 gave
higher enantioselectivity than DMSO or DMF, but the reaction
proceeded slowly (Runs 3 and 4). Acetonitrile gave a poor result
Finally, we demonstrated a successful Michael addition with
various Michael acceptors using cyclohexanone as a Michael do-
nor. As is evident from the successful results shown in Table 3,9
(S)-homoproline is quite effective in many instances and produc-
(
Run 5). Using alcohols as a solvent improved both the chemical
yield and optical yield (Runs 6–9). MeOH gave the correspond-
ing Michael adduct in 19% chemical yield with 32% optical
Copyright ꢀ 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
963
Table 2. (S)-Homoproline-catalyzed asymmetric Michael addi-
a
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
tion with various Michael donors
2
0 mol%
2
0 mol%
References and Notes
CO H
HCl
2
/ Et N
1
2
3
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N
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O
Ph
•
H
NO2
R1
+
NO2
R1
Ph
t-BuOH / r t
R2
R2
Yieldb
syn: eee
anti /%
R1
R2
rrc
Run
1
Time
d
/
%
f
Me
Me
Et
Me
Me
Me
Me
24 h
24 h
8 d
8 d
5 d
71
79
68
51
54
90
61:39 (80) 93:7 72
f
g
2
57:43 (84) 92:8 73
3
—
—
92:8 90
98:2 94
g
4
Et
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g
f
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Me n-Pr
-(CH2)4-
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98:2 90
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6
20 h
—
4
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a
Molar ratio of nitrostyrene:homoproline:Et3N = 1:0.2:0.2.
Isolated yield. Regioisomeric ratio (non-terminal:terminal).
Determined by H NMR of crude product. Determined by
b
d
c
1
e
f
HPLC analysis with a chiral column. Enantiomeric excess of
terminal regioisomer in parenthesis. 20 mol % of N-methyl-
morpholine was used instead of Et3N.
g
(2003). g) J. M. Betancort, K. Sakthivel, R. Thayumanavan, F. Tanaka,
and C. F. Barbas, III, Synthesis, 2004, 1509. h) O. Andrey, A. Alexakis,
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a
tion with various Michael acceptors
2
0 mol%
2
0 mol%
CO H
HCl
2
O
N
H
/ O NMe
O
R
•
NO2
+
NO2
R
t-BuOH / r t / 20 h
5
b
syn:antic
d
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R
Yield /%
ee /%
1
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1
2
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5
C6H5
90
85
95
77
72
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88:12
84:16
96:4
94:6
94:6
90
93
96
90
77
92
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4-NCC6H4
4-MeC6H4
4-MeOC6H4
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e
6
a
Molar ratio of ketone:nitrostyrene:homoproline:N-methyl-
morpholine = 2:1:0.2:0.2. Isolated yield. Determined by
H NMR of crude product. Determined by HPLC analysis
with a chiral column. Reaction was performed for 24 h.
b
c
(
2003). k) Y. Hayashi, W. Tsuboi, M. Shoji, and N. Suzuki, J. Am. Chem.
1
d
Soc., 125, 11208 (2003). l) A. J. A. Cobb, D. M. Shaw, and S. V. Ley,
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e
es the desired products in high stereoselectivity and enantiose-
lectivity. Using 4-chloronitrostyrene and 4-cyanonitrostyrene
having an electron-withdrawing group showed higher enantiose-
lectivity (Runs 2 and 3). Nitrostyrene derivatives having an elec-
tron-donating group gave higher diastereoselectivity (Runs 4
and 5). When 2-(2-nitrovinyl)naphthalene was used as a Michael
acceptor, the corresponding Michael adduct was obtained in
6
a) T. Oriyama, K. Imai, T. Sano, and T. Hosoya, Tetrahedron Lett., 39,
3529 (1998). b) T. Sano, K. Imai, K. Ohashi, and T. Oriyama, Chem.
Lett., 1999, 265. c) T. Sano, H. Miyata, and T. Oriyama, Enantiomer,
5, 119 (2000). d) T. Oriyama, T. Hosoya, and T. Sano, Heterocycles,
52, 1065 (2000). e) T. Oriyama, H. Taguchi, D. Terakado, and T. Sano,
Chem. Lett., 2002, 26. f) D. Terakado, H. Koutaka, and T. Oriyama,
Tetrahedron: Asymmetry, 16, 1157 (2005).
D. Terakado and T. Oriyama, unpublished results.
The absolute configurations of all Michael adducts were determined by
comparison of optical rotation with reported value.4
Typical experimental procedure is as follows (Table 3, Run 1): To a
solution of (S)-homoproline hydrochloride (9.9 mg, 0.06 mmol) in
t-BuOH (0.5 mL) were added cyclohexanone (63 mL, 0.6 mmol) and N-
methylmorpholine (7 mL, 0.06 mmol). After stirred for 30 minutes, nitro-
styrene (44.8 mg, 0.3 mmol) in t-BuOH (1 mL) was added, and stirred for
additional 20 h at room temperature. The reaction was quenched with sat-
urated NH4Cl, and the aqueous layer was extracted with ethyl acetate.
The combined organic layer was dried over MgSO4, and concentrated
in vacuo. Purification of the crude product by TLC gave 2-(1-phenyl-2-
nitroethyl)cyclohexanone (66.2 mg, 0.27 mmol).
7
9% chemical yield with 92% enantiomeric excess (Run 6).
In conclusion, we have developed a novel asymmetric
7
8
Michael addition reaction of ketone to ꢀ-nitrostyrene and its
derivatives using (S)-homoproline as a chiral organocatalyst.
The reaction was performed in a highly diastereoselective and
enantioselective manner over 90% ee. Further studies to extend
the various asymmetric carbon–carbon bond-forming reactions
and to exploit the usefulness of (S)-homoproline are currently
underway in our laboratory.
9
This work was supported by a Grant-in-Aid for Scientific
Published on the web (Advance View) June 4, 2005; DOI 10.1246/cl.2005.962