Enantioselective michael reaction of malonates and αβ- unsaturated aldehydes using a trans-4-hydroxyproline derived organocatalyst

Article abstract of DOI:10.1246/cl.2010.379

Asymmetrie Michael addition of malonates to various α, βunsaturated aldehydes using an organocatalyst derived from trans-4-hydroxyproline in MeOH proceeds smoothly to afford the corresponding Michael adducts in high yields with high to excellent enantioselectivities.

Full text of DOI:10.1246/cl.2010.379

doi:10.1246/cl.2010.379
Published on the web March 13, 2010
379
Enantioselective Michael Reaction of Malonates and ¡,¢-Unsaturated Aldehydes
Using a trans-4-Hydroxyproline Derived Organocatalyst
Hisayuki Sato, Fumiaki Nagashima, and Takeshi Oriyama*
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received January 20, 2010; CL-100064; E-mail: tor@mx.ibaraki.ac.jp)
F3C
TBSO
CF3
CF3
Asymmetric Michael addition of malonates to various ¡,¢-
TBSO
TBSO
Ph Ph
OTMS
unsaturated aldehydes using an organocatalyst derived from
trans-4-hydroxyproline in MeOH proceeds smoothly to afford
the corresponding Michael adducts in high yields with high to
excellent enantioselectivities.
N
H
N
H
N
H
OTMS
OTMS
TBSO
CF3
1
2
3
Organocatalytic asymmetric Michael addition1 has widely
been used for the stereocontrolled formation of carbon-carbon
and carbon-heteroatom bonds. ¡,¢-Unsaturated compounds are
known as versatile Michael acceptors that provide important
synthetic intermediates with various nucleophiles via Michael
reaction. The organocatalytic asymmetric Michael addition of
malonates to ¡,¢-unsaturated aldehydes has been reported in
recent years.2 For example, Jørgensen et al. demonstrated that O-
TMS diarylprolinol derived from (S)-proline was an effective
organocatalyst.3 Zlotin et al. have reported that O-TMS
diphenylprolinol modified with an ionic liquid moiety can be
used four times without any decrease in activity and enantio-
selectivity.4 However, these reactions are very slow (1-4 d). Ma
et al. have mentioned asymmetric Michael reaction catalyzed by
O-TMS-protected diphenylprolinol and acetic acid in water.5 In
this case, the reaction reached completion in less than 24 h.
However, more than 20 mol % of additive was needed for the
reaction to be completed in reasonable time with high
enantioselectivity. Therefore, the design and synthesis of more
promising diarylprolinol silyl ethers6 is a significant requirement
for the organocatalytic asymmetric Michael reaction.
On the other hand, we reported the solvent-free organo-
catalytic asymmetric Michael addition of thiols to ¡,¢-unsat-
urated aldehydes using an organocatalyst derived from trans-4-
hydroxyproline in 2007.7 This reaction proceeded smoothly
without any organic solvent to give the corresponding chiral
sulfides in almost enantiomerically pure form (up to 99% ee).
We speculated that organocatalysts derived from trans-4-
hydroxyproline may be extended to the enantioselective asym-
metric Michael addition of malonates to ¡,¢-unsaturated alde-
hydes. Herein, we disclose our fruitful results of these inves-
tigations.
TBSO
Ph Ph
OH
Ph Ph
OTBS
N
H
N
H
4
5
Figure 1. Organocatalysts examined in this study.
Table 1. Catalyst screening for the asymmetric Michael
addition of diethyl malonate to cinnamaldehydea
10 mol%
EtO2C
CO2Et
organocatalyst
CHO
EtO2C
CO2Et
+
Ph
CHO
MeOH / r t / 24 h
Ph
Entry
Organocatalyst
Yield/%b
Ee/%c
1
2
3
4d
5
1
2
3
3
4
5
1
1
1
94
90
62
80
53
75
98
74
67
97
94
92
94
62
98
97
96
97
6
7e
8f
9g
aUnless otherwise specified, the reactions were performed
using cinnamaldehyde (0.45 mmol), diethyl malonate (0.3
mmol), and organocatalyst (0.03 mmol) in MeOH (0.5 mL).
bIsolated yields. cEe was determined by HPLC analysis using a
chiral column after oxidation to the corresponding methyl
e
ester.3 dThe reaction was carried out for 48 h. The reaction
f
was performed in MeOH (0.3 mL) for 3 h. The reaction was
g
carried out with 5 mol % catalyst for 12 h. The reaction was
carried out at 0 °C for 3 h.
First, we examined the reaction of cinnamaldehyde (0.45
mmol) with diethyl malonate (0.3 mmol) in MeOH as a model
combination to optimize the organocatalyst (Figure 1 and
Table 1). Organocatalyst 1 was found to be the most effective
for this reaction (Entry 1). While a higher enantioselectivity was
obtained with organocatalyst 3, the chemical yield of Michael
adduct was much lower compared to organocatalyst 1 (Entry 3).
In the case of using organocatalyst 3, a longer reaction time was
required (Entry 4). In the presence of organocatalyst 4, which
has a free hydroxy group, yield and enantioselectivity of the
Michael adduct were reduced (Entry 5). The reaction catalyzed
by organocatalyst 5 also afforded the corresponding Michael
adducts with 98% ee (Entry 6). When the reaction was carried
out at 1.0 M, the chemical yield of the Michael adduct increased
and the reaction was completed in 3 h (Entry 7). Decreasing the
catalyst loading from 10 to 5 mol % resulted in a lower product
yield (Entry 8). A reaction carried out at 0 °C did not improve
the enantioselectivity (Entry 9).
Next, we investigated the effect of solvents in the presence
of organocatalyst 1 (Table 2). As shown in Table 2, polar protic
solvents, like MeOH and EtOH were effective and led to high
enantioselectivities (Entries 1 and 2), whereas DMF, CH3CN,
CH2Cl2, and hexane were not effective from the viewpoint of
Chem. Lett. 2010, 39, 379-381
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

380
Table 2. Effect of solventsa
Table 3. Asymmetric Michael addition of malonates to various
enalsa
10 mol%
10 mol%
TBSO
Ph Ph
TBSO
Ph Ph
OTMS
N
EtO2C
Ph
CO2Et
CHO
H
OTMS
N
CHO
Ph
EtO2C
CO2Et
+
R1O2C
R2
CO2R1
CHO
H
R1O2C
CO2R1
+
Solvent / r t / 3 h
CHO
R2
MeOH / r t
Entry
Solvent
Yield/%b
Ee/%c
Entry R1
R2
Time/h Yield/%b Ee/%c
1
2
3
4
5
6
7
MeOH
EtOH
DMF
CH3CN
CH2Cl2
hexane
neat
98
70
8
9
4
97
97
96
90
95
94
97
1
2
3
4
5
6
7
8
9
10
11
12
13
Me
Et
Bn
Ph
Ph
Ph
3
3
3
6
6
6
6
6
6
97
98
87
86
73
85
87
88
87
77
76
30
42
94
97
94
87
95
92
91
95
98
95
92
82
79
Me o-MeOC6H4
Et o-MeOC6H4
Bn o-MeOC6H4
Et p-MeOC6H4
Me o-NO2C6H4
8
46
aUnless otherwise specified, the reactions were performed
using cinnamaldehyde (0.45 mmol), diethyl malonate (0.3
mmol), and organocatalyst 1 (0.03 mmol) in MeOH (0.3 mL).
bIsolated yields. cEe was determined by HPLC analysis using a
chiral column after oxidation to the corresponding methyl
ester.3
Et
Bn
Et
Me
Bn
o-NO2C6H4
o-NO2C6H4
p-NO2C6H4
2-Furyl
6
6
13
48
Me
chemical yields (Entries 3-6). A similar solvent effect was
observed in the Jørgensen’s paper.3 Interestingly, the desired
Michael adduct was obtained in 46% yield with 97% ee under
solvent-free conditions (Entry 7).
b
aAll reactions were performed at a 0.3 mmol scale. Isolated
c
yields. Ee was determined by HPLC analysis using a chiral
column after oxidation to the corresponding methyl ester.3
A variety of reactions were conducted under optimized
conditions in the presence of 10 mol % of organocatalyst 1 in
MeOH at room temperature to establish the scope and
limitations of the present Michael reaction (Table 3).8 Using
dimethyl and dibenzyl malonates as Michael donors with
cinnamaldehyde caused reactions to occur readily (Entries 1
and 3). The reaction of aromatic ¡,¢-unsaturated aldehydes
substituted with electron-donating (OMe) and electron-with-
drawing groups (NO2) afforded the corresponding Michael
adduct in good to high yields with high enantioselectivities
(Entries 4-11). It is notable that ortho substituted aromatic ¡,¢-
unsaturated aldehydes were found to be more effective in the
enantioselectivity (Entries 5 vs. 7 and 9 vs. 11). This result might
arise from steric hindrance between enals and two silyloxy
groups of the organocatalyst molecule. Furthermore, heteroar-
omatic and aliphatic ¡,¢-unsaturated aldehydes performed well
in the presence of 10 mol % of organocatalyst 1. Unfortunately, a
longer reaction time was required for these aldehydes and the
Michael adducts were obtained in moderate yields with good
enantioselectivities (Entries 12 and 13).
In summary, we have developed a highly enantioselective
Michael addition of malonates to various ¡,¢-unsaturated
aldehydes in the presence of an organocatalyst derived from
trans-4-hydroxyproline in MeOH. In contrast to known meth-
ods, the reaction proceeds smoothly in a shorter reaction time to
afford the corresponding Michael adducts with excellent
enantioselectivities (up to 98% ee). Further studies on the
development of environmentally benign reactions using organo-
catalysts derived from trans-4-hydroxyproline are currently in
progress in our laboratory.
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A general experimental procedure is as follows: Diethyl
malonate (45.5 ¯L, 0.3 mmol) was added to a solution of
organocatalyst 1 (13.7 mg, 0.03 mmol) and cinnamaldehyde
(57 ¯L, 0.45 mmol) in MeOH (0.3 mL) at room temperature.
After being stirred for 3 h, the resultant mixture was purified
by silica gel thin-layer chromatography (AcOEt:hexane =
1:3) to provide (R)-2-(3-oxo-1-phenylpropyl)malonic acid
diethyl ester in 98% yield. The product gave satisfactory
NMR and IR spectra. The product was not so stable. Ee was
determined by HPLC analysis using a chiral column after
oxidation to the corresponding methyl ester (see: Ref. 3).
HPLC conditions: Daicel Chiralpak AD, i-PrOH:hexane =
1:4, flow rate = 0.5 mL min¹1, tR = 13.0 min (major), 19.7
min (minor), 97% ee.
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8
Chem. Lett. 2010, 39, 379-381
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/