An amino acid co-catalyzed asymmetric aldol reaction

Article abstract of DOI:10.1246/cl.2003.524

A series of chiral amino acids were found to be effective catalysts in an asymmetric aldol reaction between 4-nitrobenz-aldehyde and acetone. Lewis acids and bases were found to effectively promote this reaction. Enantioselectivities greater than 74% (ee)

Full text of DOI:10.1246/cl.2003.524

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24
Chemistry Letters Vol.32, No.6 (2003)
An Amino Acid Co-catalyzed Asymmetric Aldol Reaction
ꢀ
Ming Z. Gao, Jian Gao, Benjamin S. Lane, and Ralph A. Zingaro
Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, U. S. A.
(Received February 4, 2003; CL-030105)
A series of chiral amino acids were found to be effective
Table 1. L-valine catalyzed aldol reaction; amino acid and
metal concentration are 30 mol% and 10 mol% respectively
catalysts in an asymmetric aldol reaction between 4-nitrobenz-
aldehyde and acetone. Lewis acids and bases were found to ef-
fectively promote this reaction. Enantioselectivities greater than
74% (ee) and product yields over 85% were achieved under op-
timum conditions.
Entry
Lewis acid
2
Yield%a
ee %b,c
þ
1
2
3
Cd
Zn
4
0
4
2þ
38
50
33
25
28
51
21
56
49
47
3
þ
La
2þ
4
5
6
Ni
þ
The aldol reaction is one of the most important carbon-car-
bon bond-forming reactions in synthetic organic chemistry. In-
vestigation of this fundamental asymmetric reaction is impor-
tant in understanding other carbon–carbon bond-forming
reactions such as the Diels-Alder and Michael reactions. Earlier
investigations indicate that useful catalytic systems include: 1) a
reaction promoted by stoichiometric amounts of a chiral aux-
Ag
Fe
3þ
a
Isolated after column chromatography.
Determined by chiral HPLC analysis (Chiralpak AD col-
b
umn) and specific rotation.
c
Product configuration is R (compared with ref. 6).
1
2
iliary, 2) chiral Lewis acid-catalysis, chiral Lewis base-cata-
3
effective with respect to both yield and ee. These results are
in agreement with the relationship known to exist between
the enantioselectivity of the product and the chirality of
the catalyst. It is interesting to note Entries 1 and 6 in
Table 2 that an L-configuration of the amino acid always re-
sults in the formation of the R product, while the D-amino
acid configuration leads to the S product. This result sug-
gests that a complex transition state involving the amino
acid is formed during the reaction. The observation of the
change in ee which occurs under varied metal ion concentra-
tions (Table 1, Entry 2 and Table 2, Entry 1), motivated the
following investigation designed to study the influence of
Lewis acid concentration upon the enantioselectivity of
the reaction.
lyzed aldol reaction, 3) the heteronuclear Lewis acid-catalyzed
4
direct aldol reaction, 4) aldol enzymes and antibody-catalyzed
5
systems.
Recently, a proline catalyzed aldol reaction has been re-
ported.6{8 However, other amino acids have not been investi-
gated. This was the motivation for the current research. Herein
is reported a successful aldol reaction catalyzed by several chi-
ral amino acids together with Lewis acids or bases serving as
co-catalysts.
The reported aldol addition takes place between acetone
and 4-nitrobenzaldehyde (Scheme 1) in which acetone is a com-
ponent of a solvent system with anhydrous DMSO (DMSO:ace-
tone = 4:1). A large excess of acetone was used in the reaction
in order to promote an equilibrium favoring the aldol addition
product.
The effect of Zn2 was studied in this investigation (Table
þ
ꢁ
3). The reaction temperature was maintained at 25 C and the
concentration of amino acid was 30 mole percent. When the
Lewis acid concentrations were increased from 0% to 30%,
the product yield increased from 5% to 78%; however, the en-
antioselectivity decreased drastically. This may be attributed to
the fact that the rapid reaction rate which is achieved at high
concentrations of Zn(II) reduces the stereoselectivity. In the ab-
sence of Lewis acid, the product yield is greatly reduced. This
OH
*
O
O
Catalyst 30 mol%
DMSO, MS 4A
O2N
O2N
CHO
+
R - 1
Scheme 1.
L-valine was first investigated as a catalyst for this reac-
tion (Table 1). It was found that after stirring the homoge-
neous mixture for 48 h at room temperature, the reaction
catalyzed by L-valine and Lewis acid (metal ions) resulted
in a significant formation of the new product, 25–50% pro-
duct yield, characterized to be b-hydroxyketone 1 resulting
Table 2. Exploration of various amino acid as catalyst of the
aldol reaction. [Zn ] = 30 mol%
2þ
Yield
%
Product
configuration
Entry
Catalyst
ee %
9
from the cross-aldol reaction. Chiral-phase HPLC analyses
1
2
3
4
L-/D-Valine
L-Cysteine
L-Cystine
L-Leucine
L-Glutamic
acid
78/77
43
42
21/20
15
11
R/S
R
indicated that 1 was formed in ca. 50% ee when a divalent
metal ion served as the co-catalyst. Trivalent and monova-
lent metal ions gave either low product yields or low ee val-
ues, indicating that the Lewis acid plays an important role in
this reaction.
Considering the influence of the chirality of amino acids
upon the ee, a series of commercially available amino acids
was investigated (Table 2). L-valine was found to be the most
R
72
19
R
5
6
67
11
R
L-/D-
Phenylglycine
64/61
16/14
R/S
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.6 (2003)
525
Table 3. Influence of [Zn2 ] on the product ee value and yield
þ
Table 5. Co-catalysed aldol reaction with substituted benzalde-
hydes. [L-valine] = 30 mol%, trans-2, 5-dimethylpiperazine
2
þ
]
Entry
[Zn
Yield %
ee %
=
30 mol%
mol%
1
2
3
4
5
30
20
15
78
57
4
51
5
21
36
8
Entry
Benzal dehyde
Yield%
82
ee %
68
4
7
O N
CHO
2
1
10
38
0
—
CHO
2
3
4
79
70
80
67
74
63
O N
2
Table 4. Co-catalytic effects of Lewis bases on the aldol reac-
tion. [L-valine] = 30 mol%
CHO
NO2
Entry
Lewis base
Base
mol%
Yield %
%
ee %
a
1
2
3
DABCO
DABCO
Imidazole
30
10
30
68
72
85
40
47
57
MeO
CHO
4
5
6
Imidazole
10
78
59
References and Notes
S. Hanessian, A. Gomtsyan, and N. Malek, J. Org. Chem.,
5, 5623 (2000).
TDMPEb
TDMPE
30
10
82
73
68
70
1
6
a
DABOC denotes 1, 4-diazabicyclo[2.2.2]octane
trans-2,5-Dimethylpiperazine
2
3
S. G. Nelson, Tetrahedron: Asymmetry, 9, 357 (1998).
S. E. Denmark and R. A. Stavenger, J. Am. Chem. Soc., 122,
b
8
4N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, and M.
837 (2000).
illustrates the importance of the Lewis acid in this reaction.
It was also found that some Lewis bases can promote this
reaction under the conditions similar to those described in
Table 1, but varying concentrations of Lewis base instead of
metal ions. The results (Table 4) show that high concentrations
of Lewis bases increase the yield, but have a somewhat unfavor-
able effect on ee. In the presence of trans-2,5-dimethylpipera-
zine (Entry 6) ee value reach a maximum value of 70%.
As an extension of the work, several substituted benzalde-
hydes were examined in this reaction with L-Valine serving as
the catalyst and the Lewis base, trans-2,5-dimethylpipera-
zine as a co-catalyst. The experimental results are summa-
rized in Table 5. A high enantioselectivity is found for 2-ni-
trobenzaldehyde with a 74% ee (Entry 3) with a product
yield of 70%.
Shibasaki, J. Am. Chem. Soc., 121, 4168 (1999).
T. D. Machajewski and C. H. Wong, Angew. Chem., Int. Ed.
Engl., 39, 1352 (2000).
K. Sakthivel, W. Notz, T. Bui, and C. F. Barbas, J. Am.
Chem. Soc., 123, 5260 (2001).
5
6
7
8
B. List, P. Pojar, and C. Castello, Org. Lett., 3, 573 (2001).
B. List, R. A. Lerner, and C. F. Barbas, J. Am. Chem. Soc.,
122, 2295 (2000).
9
General procedure for the aldol reaction: to a mixture of an-
hydrous DMSO (8 mL), 4A Molecular Sieve (MS) and ke-
tone (2 mL) was added the corresponding amino acid
(0.3 mmol) and ZnBr or TDMPE (0.1–0.3 mmol). The mix-
2
ture was vigorously stirred for 4h and was followed by the
addition of 4-nitrobenzaldehyde (1 mmol). The resulting
mixture was stirred at rt. for an additional 48 h and was then
treated with aqueous solution of saturated ammonium chlo-
ride. The aqueous layer was separated and extracted with
ethyl acetate, dried and evaporated. The pure aldol products
were separated by column chromatography (silica gel, hex-
It is difficult to derive clear mechanistic conclusions in a
complex system. In conclusion, certain commercially available
chiral amino acids can effectively promote this asymmetric al-
dol reaction, Lewis acids and bases play an important role in the
catalytic process. A more detailed mechanistic investigation
with respect to the enantioselective steps is in progress.
ane/acetone). Compound R-1: IR , 3434(OH), 1713(C=O),
n
600(Ar), 1516, 1376, 1343, 1240, 1164, 1079, 1012, 855,
1
839, 788, 748, 699, 542 cm
À1
1
The Robert A. Welch Foundation of Houston, Texas has
furnished financial in support of this research. We also thank
Dr. Kevin Burgess for assistance in the use of the chiral HPLC
equipment.
.
H NMR (CDCl ), d:
3
2.22(3H, s, CH ), 2.85(2H, d, J ¼ 6:0 Hz, CH ), 4.72 (1H,
3
2
bs, OH), 5.27(1H, dd, J ¼ 5:0, 7.0 Hz, CH), 7.54(2H, d,
J ¼ 9:0, ArH), 8.21(2H, d, J ¼ 8:0 Hz, ArH).
Published on the web (Advance View) May 20, 2003; DOI 10.1246/cl.2003.524