Primary amino acid lithium salt as a catalyst for asymmetric Michael addition of isobutyraldehyde with β-nitroalkenes

Article abstract of DOI:10.1039/b814804j

Phenylalanine lithium salt was found to be an effective catalyst for asymmetric Michael addition of isobutyraldehyde with β-nitroalkenes to give quaternary carbon-containing nitroalkanes. The Royal Society of Chemistry.

Full text of DOI:10.1039/b814804j

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COMMUNICATION
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Primary amino acid lithium salt as a catalyst for asymmetric Michael
addition of isobutyraldehyde with b-nitroalkenesw
Atsushi Sato, Masanori Yoshida* and Shoji Hara
Received (in Cambridge, UK) 26th August 2008, Accepted 30th September 2008
First published as an Advance Article on the web 16th October 2008
DOI: 10.1039/b814804j
Phenylalanine lithium salt was found to be an effective catalyst
for asymmetric Michael addition of isobutyraldehyde with
b-nitroalkenes to give quaternary carbon-containing nitroalkanes.
First, we attempted Michael addition of isobutyraldehyde (1)
with trans-b-nitrostyrene (2a) using L-phenylalanine; however,
no reaction was observed (Table 1, entry 1). We assumed that
the addition of L-phenylalanine to 1 did not occur well, because
L-phenylalanine firmly forms a zwitterion, BnCH(NH3+)COOꢀ,
in the reaction conditions. Therefore, in order to increase the
basicity, we treated L-phenylalanine with an equimolar base to
prepare an L-phenylalanine metal salt, Phe-OM.6 To our delight,
we found that reaction of 1 with 2a proceeded to give the
Michael adduct 3a with high enantioselectivity in the presence
of L-phenylalanine alkaline metal salts or a magnesium salt
(Table 1, entries 2–7).6 The best result was obtained when
L-phenylalanine lithium salt was used as a catalyst (92% yield
with 94% ee); however, the reaction rate was reduced when a
larger alkaline metal salt was used. L-Phenylalanine methyl ester
was also employed as a catalyst; however, the starting material 2a
was recovered (Table 1, entry 8). These results can be explained
as follows: the lithium cation behaves as a Lewis acid to aid the
formation of enamine between the catalyst and 1 as shown in
eqn (1).7 Although an attack of an enolate of 1 can produce 3a,
the enamine mechanism seems to be preferable, since the use of a
stronger base than the lithium salt resulted in a slow reaction
rate.2,4,8
It is an undeniable fact that amino acids are extremely important
organic compounds in nature, since they are constituent elements
of proteins, which are the essence of life. Since the end of the last
century, amino acids and their analogues have been attracting
the attention of organic chemists as asymmetric catalysts, be-
cause organocatalysts have advantages in handling, environmen-
tal safety and operation costs compared with transition metal
catalysts.1 In organocatalysis based on the formation of imi-
niums or enamines from carbonyl compounds, secondary
amines, especially proline and its derivatives or MacMillan’s
imidazolidinones, have been generally used as catalysts, while
little attention has been paid to primary amines as catalysts.2
Since a variety of optically active compounds can be obtained
cheaply from a commercial source, we have studied the develop-
ment of a new asymmetric catalyst using primary amino acids.
The Michael addition of enolates to nitroalkenes is a widely
used method for obtaining enantioenriched nitroalkanes, and
many successful organocatalytic methods have been reported in
the past decade.3,4 However, the construction of a quaternary
carbon center by Michael addition of a-branched carbonyl
compounds with nitroalkenes is still a challenging subject.5 As
a pioneering work, Tanaka and Barbas’s group reported that
Michael addition of isobutyraldehyde with trans-b-nitrostyrere
was catalyzed by (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine/
TFA to give the corresponding Michael adduct in 87% yield
with 80% ee.5e Although several groups have attempted reaction
of isobutyraldehyde with trans-b-nitrostyrene, only two groups
succeeded in improving the enantioselectivity to over 90% ee:
Jacobsen’s group5f obtained 99% ee with a chiral primary amine
thiourea catalyst and Wang’s group5l,m obtained 90% ee with a
pyrrolidine sulfonamide catalyst. We found that L-phenylalanine
lithium salt, which can be readily prepared from L-phenylalanine
and lithium hydroxide, was highly effective in the Michael
addition of isobutyraldehyde with trans-b-nitrostyrene. Interest-
ingly, we obtained the Michael adduct as an (S)-enriched
enantiomer5q with a configuration opposite to that reported by
Jacobsen, Wang, Tanaka and Barbas. In this communication,
we report the details of our investigations.
ð1Þ
Table 1 Michael addition of 1 with 2a in the presence of Phe-OM
Entry
M
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8c
H
Li
Na
K
Rb
Cs
MgBr
Me
n.r.
92
84
73
60
22
11
n.r.
—
94
83
88
84
92
92
—
Division of Chemical Process Engineering, Graduate School of
Engineering, Hokkaido University, Sapporo, 060-8628, Japan.
E-mail: myoshida@eng.hokudai.ac.jp; Fax: +81 11 706 6557;
Tel: +81 11 706 6557
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b814804j
a
b
Isolated yield based on 2a. Determined by chiral HPLC analysis
c
with a DAICEL CHIRALCEL OD–H column. Freshly prepared
Phe-OMe was used as a catalyst.
ꢁc
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Table 2 Solvent screen for Michael addition of 1 with 2a
Table 4 Optimization of reaction conditions
Entry
Solvent
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
DMSO
DMF
CH3CN
Acetone
AcOEt
THF
14
18
90
82
96
95
86
93
92
88
82
76
43
58
90
85
86
83
86
92
94
94
93
86
Entry
R
T/1C
t/h
Yielda (%)
eeb (%)
1
Ph
Ph
Ph
25
25
0
25
0
25
0
25
0
5
92, 3a
85, 3a
82, 3a
88, 3b
49, 3b
86, 3c
81, 3c
87, 3d
72, 3d
71, 3e
8,e 3f
94 (S)
93 (S)
98 (S)
93d
2c
3
10
72
6
72
4
72
5
72
72
120
120
4
5
6
7
8
9
10
11
12
p-MeOC6H4
p-MeOC6H4
p-BrC6H4
p-BrC6H4
p-FC6H4
p-FC6H4
Furan-2-yl
cyclo-C6H11
PhCH2CH2
98d
Et2O
CHCl3
CH2Cl2
(CH2Cl)2
Toluene
Hexanes
94 (S)
99 (S)
95d
9
10
11
12
99d
0
25
25
96 (S)
88d
a
b
Isolated yield based on 2a. Determined by chiral HPLC analysis
with a DAICEL CHIRALCEL OD-H column.
41,f 3g
88d
a
b
Isolated yield based on 2. Determined by chiral HPLC analysis
with a DAICEL CHIRALCEL OD-H or CHIRALPAK AD-H
c
column. In parentheses, absolute configuration of 3. The amount
Next, we examined a solvent screen with Phe-OLi as shown in
Table 2. The Michael addition of 1 with 2a in a strongly
polarized solvent, DMSO or DMF, gave the Michael adduct
3a in low yields with low enantioselectivity (Table 2, entries 1 and
2). In CH3CN, acetone, AcOEt, THF and Et2O, the Michael
reaction gave 3a in high yields with moderate enantioselectivity
(Table 2, entries 3–7). When weakly polarized solvents, CHCl3,
CH2Cl2, 1,2-dichloroethane and toluene, were used, the enantio-
selectivity was improved to over 90% ee (Table 2, entries 8–11).
Hexanes gave relatively poor results due to the low solubility of
2a and the catalyst in the solvent (Table 2, entry 12). Since the
best result was obtained in CH2Cl2 (92% yield with 94% ee), we
chose CH2Cl2 as a solvent for further investigations.
d
of 1 was reduced to 1.2 equiv. The absolute configuration was not
e
determined. 59% of 2f was recovered. 18% of 2g was recovered.
f
lithium salt did not show catalytic activity under the reaction
conditions (Table 3, entries 11 and 12). We prepared an
O-silylated tyrosine lithium salt and used it as a catalyst
(Table 3, entry 13).9 The silylated catalyst was very soluble
in CH2Cl2; however, no enhancement of the reaction rate and
enantioselectivity was observed.
By using Phe-OLi as a catalyst, we investigated more
detailed reaction conditions as shown in Table 4. The reaction
of 1 with 2a completed within 5 h at 25 1C (Table 4, entry 1).
Although a longer reaction time was required, the amount of 1
could be reduced to 1.2 equivalent to 2a without considerable
loss of yield and enantioselectivity of the product 3a (Table 4,
entry 2). When the reaction was carried out at 0 1C, the
enantioselectivity was improved to 98% ee (Table 4, entry
3). Although the Michael addition of 1 with p-methoxy-trans-
b-nitrostyrene (2b) did not complete within 72 h at 0 1C, the
Michael adduct 3b was obtained in 49% yield with 98% ee
(Table 4, entry 5). When p-bromo- and p-fluoro-trans-b-
nitrostyrene (2c,d) were used as starting materials, the Michael
adducts 3c,d were obtained in high yields with 99% ee,
respectively (Table 4, entries 7 and 9). A heteroaromatic
nitroalkene, 2-(trans-2-nitroethenyl)furan (2e), was also a
good substrate (Table 4, entry 10). Unfortunately, the Michael
addition reaction using aliphatic nitroalkenes 2f,g were very
slow even at 25 1C and gave the corresponding Michael
adducts 3f,g with many minor by-products (Table 4, entries
11 and 12).
As shown in Table 3, other readily obtainable amino acid
lithium salts were evaluated for the Michael addition of 1 with
2a. Relatively bulky amino acids, L-phenylalanine, L-valine,
D-phenylglycine and L-tert-leucine, gave 3a with over 90% ee
(Table 3, entries 1–3 and 6). Interestingly, proline and its
Table 3 Catalyst screen for Michael addition of 1 with 2a
Entry
Catalyst
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Phe-OLi
Val-OLi
D-PhenylGly-OLi
Leu-OLi
iso-Leu-OLi
tert-Leu-OLi
Ala-OLi
Try-OLi
Met-OLi
Ser-OLi
Pro-OLi
Pro
O-TBS-Tyr-OLi
92
89
92
93
95
80
70
90
91
32
Trace
n.r.
80
94
94
94c
80
88
93
87
84
78
67
—
—
94
9
10
11
12
13
a
b
Isolated yield based on 2a. Determined by chiral HPLC analysis
c
with a DAICEL CHIRALCEL OD-H column. (R)-3a was obtained.
Fig. 1 Plausible transition state.
ꢁc
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A plausible transition state is shown in Fig. 1. As shown in
eqn (1), it is likely that Michael addition proceeds via an
enamine mechanism.2,4,8 The benzyl group of the enamine
occupies the opposite side of the isobutenyl group to avoid a
steric hindrance; therefore, the carboxylate group blocks one
side of the enamine. The nitrostyrene approaches from the less
hindered side of the enamine to occupy the most stable gauche
conformation.10 By an electrostatic interaction between the
partially positive nitrogen atom of enamine and the partially
negative nitro group, the enamine attacks the Re face of the
nitrostyrene to generate the (S)-3a.4a,c,5
J., 2006, 12, 5383; (c) Y. Xu and A. Co
´
rdova, Chem. Commun.,
2006, 460; (d) H. Huang and E. N. Jacobsen, J. Am. Chem.
Soc., 2006, 128, 7170; (e) S. B. Tsogoeva and S. Wei, Chem.
Commun., 2006, 1451.
5 Organocatalytic asymmetric Michael addition of a-branched car-
bonyl compounds with nitroalkenes: (a) Y. Hayashi, H. Gotoh,
T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212;
(b) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka and
C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 4966; (c) S. Luo,
X. Mi, L. Zhang, S. Liu, H. Xu and J.-P. Cheng, Angew. Chem.,
Int. Ed., 2006, 45, 3093; (d) T. Mandal and C.-G. Zhao, Tetra-
hedron Lett., 2007, 48, 5803; (e) N. Mase, R. Thayumanavan,
F. Tanaka and C. F. Barbas, III, Org. Lett., 2004, 6, 2527;
(f) M. P. Lalonde, Y. Chen and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2006, 45, 6366; (g) F.-Z. Peng, Z.-H. Shao, B.-M. Fan,
H. Song, G.-P. Li and H.-B. Zhang, J. Org. Chem., 2008, 73, 5202;
(h) S. H. McCooey and S. J. Connon, Org. Lett., 2007, 9, 599;
(i) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo,
B. M. Foxman and L. Deng, Angew. Chem., Int. Ed., 2005, 44,
105; (j) M. T. Barros and A. M. F. Phillips, Eur. J. Org. Chem.,
2007, 178; (k) Y. Li, X.-Y. Liu and G. Zhao, Tetrahedron:
Asymmetry, 2006, 17, 2034; (l) W. Wang, J. Wang and H. Li,
Angew. Chem., Int. Ed., 2005, 44, 1369; (m) J. Wang, H. Li, B. Lou,
L. Zu, H. Guo and W. Wang, Chem. Eur. J., 2006, 12, 4321;
(n) L. Zu, J. Wang, H. Li and W. Wang, Org. Lett., 2006, 8, 3077;
(o) O. Andrey, A. Alexakis, A. Tomassini and G. Bernardinelli,
Adv. Synth. Catal., 2004, 346, 1147; (p) C.-L. Cao, M.-C. Ye,
In summary, we found that readily obtainable L-phenyl-
alanine lithium salt was very effective in the Michael addition
of isobutyraldehyde with trans-b-nitroalkenes to form
quaternary carbon-containing nitroalkanes in high yields with
high enantioselectivity. Further study of asymmetric organo-
synthesis using amino acid salt by our group is under way.
This work was partly supported by the Global COE Pro-
gram (Project No. B01: Catalysis as the Basis for Innovation
in Materials Science) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan
X.-L. Sun and Y. Tang, Org. Lett., 2006, 8, 2901; (q) S. Mosse
A. Alexakis, Org. Lett., 2006, 8, 3577.
´
and
Notes and references
6 Yamaguchi reported L-proline rubidium salt was effective in the
Michael addition of malonate with a,b-unsaturated ketones or a,b-
unsaturated aldehydes, although lithium salts of L-proline and L-
valine gave poor results: (a) M. Yamaguchi, N. Yokota and
T. Minami, J. Chem. Soc., Chem. Commun., 1991, 1088;
(b) M. Yamaguchi, T. Shiraishi and M. Hirama, J. Org. Chem.,
1996, 61, 3520; (c) M. Yamaguchi, T. Shiraishi and M. Hirama,
Angew. Chem., Int. Ed. Engl., 1993, 32, 1176.
1 For reviews, see: (a) H. Pellissier, Tetrahedron, 2007, 63, 9267;
(b) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43,
5138; (c) A special issue on asymmetric organocatalysis, Acc.
Chem. Res., 2004, 37, 487; (d) A. Berkessel and H. Gro
Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005.
¨
ger,
2 A review on organocatalysis using a primary amino acid was
published recently, see: L.-W. Xu and Y. Lu, Org. Biomol. Chem.,
2008, 6, 2047.
7 Lewis Acids in Organic Synthesis, ed. H. Yamamoto, Wiley-VCH,
Weinheim, 2000.
8 S. S. V. Ramasastry, H. Zhang, F. Tanaka and C. F. Barbas, III,
J. Am. Chem. Soc., 2007, 129, 288.
3 Review on asymmetric Michael additions to nitroalkenes:
O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem.,
2002, 1877.
4 Asymmetric Michael addition with nitroalkenes using primary
amine catalyst: (a) Y. Xu, W. Zou, H. Sunde
A. Cordova, Adv. Synth. Catal., 2006, 348, 418; (b) A. Co
W. Zou, P. Dziedzic, I. Ibrahem, E. Reyes and Y. Xu, Chem. Eur.
´
n, I. Ibrahem and
9 D. Hazelard, H. Ishikawa, D. Hashizume, H. Koshino and
Y. Hayashi, Org. Lett., 2008, 10, 1445, and references therein.
10 D. Seebach and J. Golinski, Helv. Chim. Acta, 1981, 64, 1413.
´
´
´
rdova,
ꢁc
This journal is The Royal Society of Chemistry 2008
6244 | Chem. Commun., 2008, 6242–6244