Homodiphenylprolinol methyl ether as a highly efficient catalyst for asymmetric Michael addition of ketones to nitroalkenes

Article abstract of DOI:10.1055/s-0029-1217185

A series of novel homoprolinol analogues and ethers were developed and evaluated in direct Michael addition of ketones to nitroalkenes. Excellent yields (up to 99%), diastereoselectivities (up to 98% dr) and enantioselectivities (up to 98% ee) were achiev

Full text of DOI:10.1055/s-0029-1217185

LETTER
1457
Homodiphenylprolinol Methyl Ether as a Highly Efficient Catalyst for
Asymmetric Michael Addition of Ketones to Nitroalkenes
Catalyst for
A
h
M
i
ichael
-
Addition
W
of
K
etones to
N
itroalk
eenes n Wang, Jun Chen, Gui-Hua Chen, Yun-Gui Peng*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. of China
Fax +86(23)68254000; E-mail: pyg@swu.edu.cn
Received 30 January 2009
ficiency and only need 0.5–2 mol% catalysts loads.9c The
catalyst worked well even for the ‘simplest’ nucleophile
acetaldehyde, as reported by List9d and Hayashi9e inde-
pendently. However, poor reactivities were observed with
Abstract: A series of novel homoprolinol analogues and ethers
were developed and evaluated in direct Michael addition of ketones
to nitroalkenes. Excellent yields (up to 99%), diastereoselectivities
(up to 98% dr) and enantioselectivities (up to 98% ee) were
achieved in the presence of 5 mol% homodiphenylprolinol methyl this catalyst when ketones were used as substrates. It ap-
ether as catalyst and 5 mol% o-methylbenzoic acid as the additive
at room temperature.
pears that the steric bulkiness of the diphenyltrimethylsi-
loxymethyl group circumvents the efficient formation of
Key words: homodiphenylprolinol methyl ether, organocatalyst,
asymmetric Michael addition, ketone, nitroolefin
the enamine intermediate with ketones, resulting in poor
reactivities.
We have previously developed pyrrolidine-based silyl
ether 210 as organocatalysts for direct Michael reaction of
ketones to nitroalkenes by properly adjusting the size of
the shielding group and its distance from the second
amine. Although high levels of enantioselectivity (73–
95% ee) and diastereoselectivity ( 20:1 dr) were
achieved, the catalytic efficiency was low (up to 20 mol%
catalyst loading).10b
Michael addition is one of the most important C–C bond-
formation reactions in organic synthesis1 and, therefore,
development of asymmetric catalysts for such a process
has been a focus of recent research efforts.2 Among the
variants of Michael addition reaction, direct addition of
carbonyl compounds to nitroalkenes appears particularly
attractive, affording versatile difunctional products in an
atom-economical manner.3 Barbas,4 List,5 and Enders6
with co-workers reported independently the first asym-
metric organocatalytic addition under the catalysis of L-
proline. However, only poor enantioselectivity was
achieved. As a result, considerable efforts have been di-
rected towards the development of an organocatalytic
asymmetric version of the Michael addition of ketones to
nitroolefins over recent years,7,8 and many improvements
of the reaction under pyrrolidine-based8 catalytic systems
have been made. Most of these catalysts bear a hydrogen-
bonding moiety, such as sulfonamide,8a,b ammonium
salt,8c–8h and thiourea8i,j in the side chain to direct the sub-
strate approach. Although desired stereoselectivities were
achieved, a loading of more than 10 mol% of catalysts
was required, and the development of highly efficient
chiral catalysts is still in great demand for the Michael ad-
dition of ketones to nitroolefins.
Ph
Ph
OTMS
O
Ph
Si
Ph
N
N
H
H
1
2
Figure 1
With an interest in developing an efficient chiral organo-
catalytic system to achieve both high yield and enantiose-
lectivity in Michael additions, we designed and
synthesized new chiral organic catalysts 3 in which the
size of the shielding group and its distance from the nitro-
gen atom were further adjusted. Herein, we report a series
of homoprolinol analogues and ethers 3a–r (Figure 2) as
organocatalysts in attaining the direct asymmetric Micha-
el addition of ketones to nitroolefins with high efficiency.
R1
R1
OR2
N
Steric factors have been widely used in the asymmetric
synthesis and catalysis as a tool of achieving stereocon-
trol.9 Such a concept has been applied in Michael addition
reactions.9a–9e Diphenylprolinol silyl ether catalyst 19f,g re-
ported by Hayashi et al. represents the most successful ex-
ample on the basis of pure steric interactions for the
asymmetric Michael reaction.9b Ma has found that catalyst
1 (Figure 1) was capable of promoting the directed Micha-
el addition of aldehydes to nitroalkenes with very high ef-
H
3a R1 = Ph; R2 = H
3j R1 = Ph; R2 = TBS
3b R1 = 4-MeC6H4; R2 = H
3c R1 = 3,5-Me2C6H3; R2 = H
3k
3l
R
R
1 = Ph; R2 = Me
1 = 4-MeC6H4; R2 = Me
3d R1 = 3,5-(F3C)2-C6H3; R2 = H
3e R1 = β-Naph; R2 = H
3m R1 = 3,5-Me2C6H3; R2 = Me
3n
3o
3p
3q
3r
R
R
R
R
1 = 3,5-(F3C)2C6H3; R2 = Me
1 = β-Naph; R2 = Me
3f
R
1 = 4-C3H7C6H4; R2 = H
3g R1 = 4-C5H11C6H4; R2 = H
1 = 4-C3H7C6H4; R2 = Me
1 = 4-C5H11C6H4; R2 = Me
3h R1 = Et; R2 = H
3i
R
1 = Ph; R2 = TES
R
1 = Ph; R2 = Et
Figure 2 Chiral catalysts tested
SYNLETT 2009, No. 9, pp 1457–1462
x
x.
x
x.
2
0
0
9
Advanced online publication: 18.05.2009
DOI: 10.1055/s-0029-1217185; Art ID: W01409ST
© Georg Thieme Verlag Stuttgart · New York
These new catalysts were then tested in the asymmetric
Michael addition reaction of cyclohexanone 4a to b-nitro-

1458
S.-W. Wang et al.
LETTER
styrene 5a. As can be seen from the results summarized in lytic activities were significantly influenced by R1. When
Table 1, the catalytic and enantioselective activities of R1 was changed from phenyl to para-methylphenyl, the
3a–r differ significantly. In the cases of 3a–h, which bear diastereoselectivity and enantioselectivity of the product
hydroxy group as hydrogen-bond donors to activate the b- remained the same, however, the reaction time was short-
nitrostyrene, the reaction proceeded to give adducts 6a ened from 48 hours to 36 hours while the yield was in-
with good diastereoselectivity (87–98% de) and enanti- creased from 78% to 94% (Table 1, entries 1 and 2).
oselectivity (87–93% ee; Table 1, entries 1–8). The cata-
Table 1 Screening of New Chiral Catalysts 3 for Asymmetric Michael Addition of Cyclohexanone 4a to b-Nitrostyrene 5a
O
O
Ph
NO2
cat. 3, solvent
NO2
+
Ph
additive, r.t.
5a
6a
4a
Entry
1d
Catalyst (%)
3a (20)
3b (20)
3c (20)
3d (20)
3e (20)
3f (20)
3g (20)
3h (20)
3i (20)
3j (20)
3k (20)
3l (20)
3m (20)
3n (20)
3o (20)
3p (20)
3q (20)
3r (20)
3k (5)
Solvent
Additive
Time (h)
48
Yield (%)a
78
dr (syn/anti)b
96:4
96:4
95:5
97:3
87:13
98:2
94:6
94:6
–
ee (%)c
93
93
85
88
93
93
94
87
–
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
toluene
CHCl3
Et2O
none
–
2d
36
94
3d
–
36
98
4d
–
72
99
5d
–
48
77
6d
–
72
83
7d
–
72
86
8d
–
48
56
9d
–
48
–
10d
11d
12d
13d
14d
15d
16d
17d
18d
19e,f
20e
21e
22e
23e
24e
25e
26e
27e
28e
29e
–
48
–
–
–
–
24
99
98:2
98:2
97:3
98:2
97:3
98:2
99:1
97:3
97:3
97:3
96:4
97:3
97:3
95:5
95:5
95:5
97:3
–
96
95
95
95
95
95
90
90
96
96
96
95
95
92
92
94
95
–
–
40
92
–
66
91
–
103
60
92
–
87
–
72
91
–
24
94
–
72
87
–
72
53
3k (5)
2-MePhCO2H
4-MePhCO2H
MeCO2H
24
99
3k (5)
24
89
3k (5)
36
99
3k (5)
4-O2NPhCO2H
2-MePhCO2H
2-MePhCO2H
2-MePhCO2H
2-MePhCO2H
2-MePhCO2H
2-MePhCO2H
72
34
3k (5)
48
95
3k (5)
48
84
3k (5)
68
59
3k (10)
3k (5)
brine
72
23
i-PrOH
DMF
48
48
trace
trace
3k (5)
–
–
Synlett 2009, No. 9, 1457–1462 © Thieme Stuttgart · New York

LETTER
Catalyst for Asymmetric Michael Addition of Ketones to Nitroalkenes
1459
Table 1 Screening of New Chiral Catalysts 3 for Asymmetric Michael Addition of Cyclohexanone 4a to b-Nitrostyrene 5a (continued)
O
O
Ph
NO2
cat. 3, solvent
NO2
+
Ph
additive, r.t.
5a
6a
4a
Entry
30e
Catalyst (%)
3k (10)
Solvent
Additive
Time (h)
11
Yield (%)a
dr (syn/anti)b
97:3
ee (%)c
96
hexane
hexane
2-MePhCO2H
2-MePhCO2H
99
86
31e
3k (2)
36
96:4
96
a Isolated yield.
b Determined by 1H NMR spectroscopy.
c Determined by chiral HPLC analysis.
d Reactions were conducted in hexane (1 mL) using 4a (5 mmol) and 5a (0.5 mmol) in the presence of 20 mol% of the catalyst at r.t. (25 °C).
e Reactions were conducted in solvent (0.5 mL) using 4a (1.25 mmol) and 5a (0.25 mmol) in the presence of equivalent amount of additive and
catalyst as shown in parenthesis at r.t. (25 °C).
f Without additive.
Further increase of the size of para substituent on the phe- also screened (Table 1. entries 20, 24–29). Good yields
nyl ring by changing methyl (3b) to propyl (3f) or pentyl and enantiomeric excesses were obtained in nonpolar or
(3g) to result a decrease in catalytic reactivity giving 83% less polar solvents such as hexane and toluene. The best
and 86% yields after 72 hours, respectively. However, the result was achieved in hexane (Table 1, entry 20). On the
diastereoselectivity and enantioselectivity changed only other hand, reactions in more polar solvent such as CHCl3,
slightly (Table 1, entries 2, 6, and 7). When R1 was Et2O, DMF, and protic solvent brine, 2-PrOH led to a de-
changed to ethyl (3h) from phenyl (3a), the catalytic ac- crease both in yields and enantioselectivities (Table 1, en-
tivity decreased dramatically, only 56% yield was ob- tries 25–29). Especially, almost no reactions were
tained after 48 hours (Table 1, entries 1 and 8). This may observed in 2-PrOH and DMF. In addition, 5% catalyst
be caused by poor solubility of the catalyst in the reaction load was enough for good reactivity, diastereoselectivity,
system. We then etherified these homoprolinol analogues and enantioselectivity (Table 1, entry 20). When the cata-
and tested the corresponding product 3i–r as catalysts in lyst load was reduced from 5% to 2%, the reactivity de-
the reaction. To our delight, the catalytic activities were creased slightly, affording only 86% yield after 36 hours;
increased dramatically when 3k11 and 3q were used as cat- with 10% catalyst load, the reactivity increased greatly,
alysts compared with their corresponding alcohol precur- affording 99% yield after 11 hours. Neither enantioselec-
sors 3a and 3g (Table 1, entries 1, 7, 11, 17). Particularly, tivity nor diastereoselectivity was significantly influenced
3k gave both good diastereoselectivity (up to 98:2) and by the catalyst load (Table 1, entries 20, 30, and 31). Good
enantioselectivity (up to 96% ee) with a yield up to 99% enantioselectivity and diastereoselectivity were obtained
after 24 hours (Table 1, entry 11). Further increase of the even with 2% catalyst load (Table 1, entry 31).
size of R2 and by changing methyl (3k) to ethyl (3r) led to
With the optimal conditions in hand, we investigated a va-
elongated reaction time (from 24 h to 72 h), decreased
riety of nitroolefins, and the results are summarized in
yields (from 99% to 87%), and loss of optical purity of the
Table 2.14 In general, b-nitrostyrenes with both electron-
withdrawing and electron-donating aryl group reacted ef-
ficiently (68–99% yield) with high diastereoselectivity
(up to 98% dr) and enantioselectivity (up to 98% ee) for
syn adduct. The substitution position of b-nitrostyrenes
had slightly influence on reactivity, diastereoselectivity,
products (from 96% ee to 90% ee; Table 1, entries 11 and
18). No reactions were observed when R2 was changed
into the bulky group TES (3i) and TBS (3j; Table 1, en-
tries 9 and 10).12 Therefore, among the catalytic systems
examined, the best catalyst was 3k.
We then studied the influence of acid additive on the reac- and enantioselectivity. For example, when the nitro group
tion (Table 1, entries 20–23). o-Methylbenzoic acid gave position of b-nitrostyrene was changed from ortho to
the optimal performance in yield, diastereoselectivity, and para, the yield decreased from 99% to 95%, and the dia-
enantioselectivity (Table 1, entry 20).13 The same good re- stereoselectivity decreased from 96% de to 92%, the
sults were obtained in the reaction with 5% catalyst, and enantioselectivity remains the same with 95% ee (Table 2,
5% o-methylbenzoic acid as 20% catalyst was used alone entries 10 and 12). The asymmetric additions of other ke-
(Table 1, entries 11 and 20). When p-nitrobenzoic acid, a tones to nitrostyrene 5a using 3k as catalyst were also in-
stronger acid, was used, the catalytic reactivity decreased vestigated. Acetone gave the desired product in 93% yield
sharply, and only 34% yield was obtained after 72 hours and with 56% ee. Cyclopentanone also worked well to
(Table 1, entry 23). p-Methylbenzoic acid and acetic acid give the desired products in excellent yield with moderate
as additives slightly decreased the catalytic reactivity and regioselectivity (65:35) and good enantioselectivity (93%
gave similar good diastereoselectivity and enantioselec- ee; Table 2, entry 24).
tivity (Table 1, entries 21 and 22). A series of solvents was
Synlett 2009, No. 9, 1457–1462 © Thieme Stuttgart · New York

1460
S.-W. Wang et al.
LETTER
Table 2 Catalytic Asymmetric Michael Addition of Ketones to Nitroolefins under Optimized Conditionsa
R3
O
O
3k cat. (5 mol%)
NO2
R1
NO2
R1
R3
+
R2
2-MeC6H4COOH (5%)
n-Hex, r.t.
R2
4
6
5
Entry
1
Time (h)
24
R1
R2
R3
Yield (%)b
97
dr (syn/anti)c
88:12
90:10
98:2
ee (%)d
91
94
98
95
95
96
96
95
97
95
95
95
98
95
97
95
95
98
93
94
91
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
2-furyl
2
72
2-thienyl
72
3
36
2-FC6H4
97
4
24
4-FC6H4
98
94:6
5
12
2-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-naphthyl
1-naphthyl
2,4-Cl2C6H3
99
96:4
6
12
99
97:3
7
12
98
97:3
8
48
72
95:5
9
12
96
97:3
10
11
12
13
14
15
16
17
18
19
20
21
12
99
96:4
12
93
90:10
92:8
12
96
48
95
94:6
24
84
96:4
48
99
97:3
24
99
96:4
64
99
95:5
48
83
99:1
36
91
99:1
12
99
96:4
72
68
99:1
O
O
22
24
Ph
86
79:21
97/89
R1
O
R2
O
23e
24e
25e
26f
48
48
42
90
H
H
Ph
93
91
97
46
–
23
-(CH2)3-
-(CH2)4-
Ph
65:35
63:37
96:4
93/93
97/98
90
n-Bu
Ph
Me
Me
a All reactions were carried out using 4 (0.75 mmol, 3 equiv) and nitroolefins (0.25 mmol, 1 equiv) in the presence of 5 mol% of catalyst 3k
and 5 mol% of o-methylbenzoic acid in hexane (0.5 mL) at r.t.
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d Enantioselectivities were determined by chiral HPLC analysis in comparison with authentic racemic material.
e The amounts of 20 mol% of 3k and 20 mol% of o-methylbenzoic acid were used.
f Another stereomer (16% yield, 84% ee) was also obtained by reaction at the methyl group.
Synlett 2009, No. 9, 1457–1462 © Thieme Stuttgart · New York

LETTER
Catalyst for Asymmetric Michael Addition of Ketones to Nitroalkenes
1461
O
Ph
Acknowledgment
O
NO2
cat. 3k (5 mol%)
The authors gratefully acknowledge the Natural Science Foundati-
on of China (NSFC 20572087 and 20872120), the Ministry of Edu-
cation, P. R. of China (No. 106141), and the Program for New
Century Excellent Talents (NCET-06-0772) in University for ge-
nerous financial support.
+
Ph
NO2
2-MeC6H4COOH (5 mol%)
n-Hex, r.t., 40 h
83% yield; 98% dr
94% ee (syn)
O
O
Ph
cat. 3k (5 mol%)
References and Notes
NO2
NO2
H
+
Ph
H
2-MeC6H4CO2H (5 mol%)
n-Hex, r.t., 12 h
(1) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992.
5a
(CH2)2Me
(CH2)2Me
84% yield, 95% dr
42% ee (syn)
(2) For reviews, see: (a) Tomioka, K.; Nagaoka, Y.;
Yamaguchi, M. In Comprehensive Asymmetric Catalysis;
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1279.
Scheme 1 Michael addition reactions of other substrates catalyzed
by 3k
The asymmetric additions of cyclohexanone to cis-
nitrostyrene and pentanal to nitrostyrene 5a using 3k as a
catalyst were also investigated. As shown in Scheme 1,
cis-nitrostyrene gave the desired product in 83% yield
with 94% ee. Pentanal also worked well to give the de-
sired products in good yield (84%) and diastereoselectiv-
ity (95% dr) but poor enantioselectivity (42% ee).
(3) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
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by acyclic synclinal transition-state model originally pro-
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for cyclohexanone, the bulky group CH2C(OMe)(Ph)2
should effectively shield the Si face of an enamine double
bond, which would make nitrostyrene acceptor approach
from the nonshielded side to give the observed major
enantiomer.
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Ph
Ph
Ph
Ph
O
N
O
N
N
N
MeO
–O
MeO
O
trans-nitrostyrene
cis-nitrostyrene
Figure 3 Proposed transition-state model
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J. Y.; Zheng, X. X.; Cheng, J. P. J. Org. Chem. 2006, 71,
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Zhao, Y. B.; Liang, Y. M. Tetrahedron: Asymmetry 2006,
17, 3288. (n) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V.
Synlett 2005, 611. (o) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F. III Synthesis
In conclusion, we have developed a novel organocatalytic
system for Michael addition of ketones to nitroalkenes,
which is composed of homodiphenylprolinol methyl ether
as the catalyst and o-methylbenzoic acid as the additive.
Only 5 mol% catalyst loading was sufficient for good
yields (up to 99%) and high stereoselectivities (up to 98%
dr and 98% ee), and only room temperature is required. It
is by far the lowest catalyst load for direct Michael reac-
tion of ketones to nitroalkenes. Further investigations of
the applications of this organocatalytic system in other
asymmetric reactions are in progress.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 9, 1457–1462 © Thieme Stuttgart · New York

1462
S.-W. Wang et al.
LETTER
2004, 1509. (p) Andrey, O.; Alexakis, A.; Tomassini, A.;
Bernardinelli, G. Adv. Synth. Catal. 2004, 346, 1147.
(q) Clarke, M. L.; Fuentes, J. A. Angew. Chem. Int. Ed. 2007,
46, 930. (r) Luo, S. Z.; Mi, X. L.; Song, L. Z.; Xu, H.;
Cheng, J. P. Angew. Chem. Int. Ed. 2006, 45, 3093. (s)Luo,
S. Z.; Mi, X. L.; Liu, S.; Xu, H.; Cheng, J. P. Chem.
Commun. 2006, 3687. (t) Almasi, D.; Alonso, D. A.; Nájera,
C. Tetrahedron: Asymmetry 2006, 17, 2064. (u) Li, P. H.;
Wang, L.; Wang, M.; Zhang, Y. C. Eur. J. Org. Chem. 2008,
1157.
2 H), 2.76–2.82 (m, 1 H), 2.87–2.94 (m, 1 H), 3.06 (s, 3 H),
7.17–7.36 (m, 10 H) ppm. 13C NMR (75.5 MHz, CDCl3):
d = 23.8, 32.1, 40.9, 45.7, 50.5, 54.5, 82.3, 126.5, 126.7,
126.8, 127.0, 127.8, 127.9, 145.3, 145.5 ppm. IR (KBr):
n = 3416, 3363, 3022, 2958, 2826, 1618, 1599, 1491, 1444,
1400, 1189, 1155, 1122, 1065, 916, 849, 752, 698, 621, 594
cm–1. HRMS (TOF): m/z calcd for C19H24NO [M + H]+:
282.1858; found: 282.1832.
Ph
Ph
NaH (5 equiv)
MeI, THF
Ph
OH
Ph
(9) (a) Mandal, T.; Zhao, C. G. Tetrahedron Lett. 2007, 48,
5803. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M.
Angew. Chem. Int. Ed. 2005, 44, 4212. (c) Zhu, S. L.; Yu,
S. Y.; Ma, D. W. Angew. Chem. Int. Ed. 2008, 47, 545.
(d) García-García, P.; Ladépêhe, A.; Halder, R.; List, B.
Angew. Chem. Int. Ed. 2008, 47, 4719. (e) Hayashi, Y.;
Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem. Int. Ed.
2008, 47, 4722. (f) Marigo, M.; Fielenbach, D.; Braunton,
A.; Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2005, 44, 3703. (g) Marigo, M.; Franzén, J.; Poulsen, T. B.;
Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
6964.
N
N
OMe
Cbz
Cbz
8b
8a
Ph
Pd/C
H2
Ph
OMe
N
H
3k
Scheme 2
(10) (a) Zhao, G. L.; Ibrahem, I.; Sundén, H.; Córdova, A. Adv.
Synth. Catal. 2007, 349, 1210. (b) Liu, F. Y.; Wang, S. W.;
Wang, N.; Peng, Y. G. Synlett 2007, 2415.
(12) The trimethyl silyl ether showed good catalytic reactivity
and slightly decreased diastereoselectivity (up to 97:3) and
enantioselectivity (up to 93% ee) compared to 3k.
Unfortunately, it was unstable and easily decomposed into
alcohol.
(13) When benzoic acid was used as cocatalyst, the same good
results were obtained at r.t. (99% yield, 96% ee and 92% dr
after 24 h). But, when the reaction proceeded at 0 °C,
benzoic acid has shown slightly lower reactivity (58% yield)
than o-methylbenzoic acid (63% yield) with the same
stereoselectivities (99% ee, 98% dr) after 48 h.
(11) The Synthesis and Characterization of the Catalyst 3k.
Compound 8a (see Supporting Information; 24.8 g, 62
mmol) was dissolved in MeI (2 mL) and THF (10 mL), NaH
(310 mmol) was added slowly to the stirred mixture over a
course of 30 min at 0 °C under N2. The reaction mixture was
then stirred overnight and quenched with H2O. Excess MeI
was removed under reduced pressure in a well-ventilated
hood. The residue was dissolved in EtOAc and partitioned
between EtOAc and H2O. The organic layers were collected,
washed with brine, dried over with MgSO4, filtered, and
concentrated to give colorless oil. The oil was eluted through
a SiO2 column by EtOAc–hexane gave pure 9a with yield
70%.
(14) Typical Procedure for the Direct Asymmetric Michael
Addition of Ketones to Nitroolefins
To a stirred solution of catalyst (0.05 equiv) in hexane (0.5
mL) and ketone (3 equiv) at r.t. was added o-methylbenzoic
acid (0.05 equiv) and, after 5 min, nitroolefin (1 equiv) was
added. The reaction mixture was stirred at r.t. for the
appropriate time. The solvent was evaporated and the
residue was chromatography on SiO2 column (hexane–
EtOAc = 10:1) to afford the desired product. The ee of the
product was determined by chiral HPLC analysis (Daicel
Chiralpak AS-H or AD-H) to compare with their
corresponding racemic peaks.
The resulting 9a was dissolved in MeOH (6 mL) and Pd/C
(20% in weight) was added. The mixture was stirred
overnight at r.t. under H2 atmosphere (1.013 bar). Then, the
mixture was filtered through Celite and the solvent
evaporated under reduced pressure to afford the crude
product, which was further purified by flash column
chromatography on SiO2 (CH2Cl2–MeOH = 90:10) to afford
the title compounds 3k (Scheme 2). White solid, mp 86–
87 °C, [a]D25 +27.0 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 1.17–1.23 (m, 1 H), 1.50–1.71 (m, 3 H), 1.90 (s,
1 H), 2.46–2.52 (dd, J = 14.2, 4.7 Hz, 1 H), 2.56–2.68 (m,
(15) Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.
Synlett 2009, No. 9, 1457–1462 © Thieme Stuttgart · New York

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