Organo-catalyzed highly diastereo- and enantio-selective direct aldol reactions in water

Article abstract of DOI:10.1016/j.tetlet.2008.03.131

The asymmetric direct aldol reactions of a wide scope of aromatic aldehydes, with unmodified ketones in the presence of 1 mol % of organocatalyst prepared from (2R,3R)-diethyl 2-amino-3-hydroxysuccinate and trans-4-hydroxy-l-proline, were performed in wat

Full text of DOI:10.1016/j.tetlet.2008.03.131

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3372–3375
Organo-catalyzed highly diastereo- and enantio-selective
direct aldol reactions in water
Jun-Feng Zhao a,b, Long He c, Jun Jiang a,b, Zhuo Tang a,b
,
Lin-Feng Cun a,b, Liu-Zhu Gong a,b,c,
*
a Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
b Graduate School of Chinese Academy of Sciences, Beijing, PR China
c Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry of Science and Technology of China,
Hefei 230026, PR China
Received 30 January 2008; revised 21 March 2008; accepted 26 March 2008
Available online 29 March 2008
Abstract
The asymmetric direct aldol reactions of a wide scope of aromatic aldehydes, with unmodified ketones in the presence of 1 mol % of
organocatalyst prepared from (2R,3R)-diethyl 2-amino-3-hydroxysuccinate and trans-4-hydroxy-L-proline, were performed in water,
affording aldol products in high yields with excellent diastereoselectivities of up to >99:1 and enantioselectivities of up to 98%.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Water; Organocatalysis; Direct aldol; Diastereo- and enantio-selective
The use of water as a solvent not only makes the reac-
tion environmentally amenable, but much safer to handle
since aqueous conditions principally avoid flammable
organic solvents and strict anhydrous conditions. The
development of efficient water-compatible reactions is of
great importance and has received increasing interests.1
Recently, organo-catalyzed reactions in water2 have
received much attention since Hayashi,3 Barbas III and
Tanaka,4 independently discovered organo-catalyzed
highly enantio-selective direct aldol reactions in pure water.
Among them, the organo-catalyzed direct aldol reaction in
water is the most studied.5 However, most of the organo-
catalyzed aldol reactions are suffering from the high cata-
lyst loading and large excess of donor that somehow sur-
passes their commercial application. Herein, we report
that as little as 1 mol % of an L-proline amide derivative
catalyzes the direct asymmetric aldol reactions between
ketones and aromatic aldehydes in water with up to
>99:1 dr and 98% ee (see Fig. 1).
Previously, we found that L-proline amides derived from
chiral amino alcohols acted as efficient catalysts for the
asymmetric direct aldol reaction in aqueous environment6
as well as in organic solvent.7 To further investigate the
L-proline amide derivatives catalyzed aldol reaction, pure
water was used as the solvent. Interestingly, all of these
O
O
TBSO
TBSO
Ph
Ph
N
H
N
H
Ph
Ph
N
H
N
H
HO
HO
2
1
O
O
CO2Et
CO2Et
CO2Et
CO2Et
N
N
N
H
N
H
H
H
HO
HO
3
4
*
Corresponding author. Tel.: +65 63168956.
Fig. 1. Organocatalysts evaluated in this study.
E-mail address: Zhao0065@ntu.edu.sg (L.-Z. Gong).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.131

J.-F. Zhao et al. / Tetrahedron Letters 49 (2008) 3372–3375
3373
Table 1
Table 2
Direct aldol reaction of cyclohexanone with 4-nitrobenzaldehyde cata-
lyzed by L-proline amide derivatives 1–4 in watera
trans-4-Hydroxy-prolinamide 4 catalyzed direct aldol reactions of 5a with
various aldehydes in watera
O
O
O
OH
O
O
OH
O
1 mol % 4
H2O, 250 C
+
+
H
1-10 mol % 1-4
R
H
R
H2O
O2N
O2N
7aa-aj
5a
6a-j
5a
6a
7aa
Entry
Catalyst
(mol %)
Temperature
(°C)
Time
(h)
Yieldb
(%)
drc
eed
(%)
Entry
R
7
Time (h) Yieldb (%) drc
eed (%)
>99:1 94
98:2 92
1
2
3
4
5
6
7
8
9
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
Ph
4-CN C6H4
4-CF3C6H4
7aa
7ab
5
8
99
95
85
75
90
93
95
80
94
50
1
2
3
4
5
1 (10)
2 (10)
3 (10)
4 (10)
4 (10)
4 (2)
4 (1)
4 (1)
4 (2)
4 (1)
0
0
0
24
24
24
4
0.25
3
89
68
41
95
99
99
99
93
75
95
60
99:1
>99:1
2:1
>99:1
>99:1
>99:1
>99:1
98:2
96
93
94
97
93
92
94
95
95
94
95
7ac 10
7ad 24
7ae 24
>99:1 95
>99:1 92
96:4
>99:1 95
>99:1 98
>99:1 93
>99:1 93
>99:1 92
0
92
25
25
25
0
7af
10
5
6
2,6-Cl2C6H4 7ag
7e
8
5
4-ClC6H4
4-BrC6H4
4-MeC6H4
7ah 24
7ai
7aj
24
72
24
30
24
24
9f
10g
11g
a
0
96:4
84:16
89:11
10
a
À5
See Ref. 8.
Isolated yield.
Determined by 1H NMR of the crude product.
4 (1)
À10
b
c
Conditions: 5a (0.5 mmol) and 6a (1.0 mmol, 2 equiv) in water
(0.5 mL).
d
Determined by chiral-phase HPLC analysis for anti-product.
b
Isolated yield.
c
d
e
f
Determined by 1H NMR of the crude product.
Determined by chiral-phase HPLC analysis.
See Ref. 8.
Donor 6a (0.5 mmol, 1 equiv) was used.
The reaction was carried out in brine.
smoothly to give the aldol adducts with excellent diastereo-
selectivities (up to >99:1) and enantioselectivities (up to
98% ee). Notably, in most cases, the diastereoselectivities
reach >99:1, much higher than those reported previ-
ously.4,5 Furthermore, not only the aromatic aldehydes
bearing electron-withdrawing groups lead to the formation
of 7aa–7aj with very high diastereoselectivities ranging
from 96:4 to >99:1 and enantioselectivities ranging from
92% to 98% ee (entries 1–9), but also the ones bearing an
electron-donating group gave extremely high diastereo-
selectivity of >99:1 and enantioselectivity of 92% ee (entry
10).
To examine the generality of the current process, the
aldol reactions between 4-nitrobenzaldehyde (6a) and dif-
ferent ketones, including cyclic and acyclic ketones (5b–k)
were tested (Table 3). As can be seen from the results sum-
marized in Table 3, the diastereo and enantioselectivities
are significantly influenced by the structure of ketones. Sur-
prisingly, although both 5b and 6a are solid and suspend-
ing in water, the reaction occurred smoothly to furnish
the desired product (7ba) in a good yield of 75% with a dia-
stereoselectivity of 90:10 and enantioselectivity of 95% ee
(Table 3, entry 2). For acyclic ketones, the enantioselectiv-
ities obtained range from 71% to 89% (Table 3, entries
3–8). Importantly, the present protocol shows high regio-
selectivity for the aldolization of unbranched ketones,
except 2-butanone, which reacted with 4-nitrobenzalde-
hyde to give a small amount of the regiomer of 7da. The
other unbranched ketones evaluated here preferentially
reacted at the methyl group, exclusively giving the corre-
sponding aldol adduct as a single product without detect-
ing its regiomer (Table 3, entries 3–8).
g
L-proline amides are indeed efficient in catalyzing direct
aldol reaction in pure water. The direct aldol reactions of
cyclohexanone with 4-nitrobenzaldehyde catalyzed by
10 mol % of 1–4 took place smoothly in water with excel-
lent diastereoselectivity and enantioselectivity (Table 1,
entries 1–4). Significantly, quantitative yield, excellent dia-
stereoselectivity (>99:1), and enantioselectivity (93%) were
obtained by performing the reaction at room temperature
for 15 min (Table 1, entry 5). In terms of the reaction rate,
diastereoselectivity and enantioselectivity, the prolinamide
derivative 4 can be considered the best catalyst. To our
delight, by using pure water as the solvent, only 1 mol %
of 4 was efficient enough to mediate the aldol reaction in
a quantitive yield with an excellent diastereomeric ratio
of >99:1 in favor of anti-diastereomer as well as a high
enantioselectivity of 94% ee (Table 1, entry 7). In contrast
to the known reaction using a large excess of donor, only 1
or 2 equiv of donor to the aldehyde was used in this case
(Table 1, entry 9). Using brine as the solvent and perform-
ing the aldol reaction at low temperature did not improve
the enantioselectivity but the yield and diastereoselectivity
were sacrificed and a prolonged reaction time was required
to ensure a complete conversion (Table 1, entries 10
and 11).
Direct aldol reactions of various substituted benzalde-
hydes with cyclohexanone were carried out in the presence
of 1 mol % 4 under the optimal conditions to examine the
scope and limitation. The results are summarized in Table
2. The aldol reactions of both electron-deficient and elec-
tron-rich benzaldehydes with cyclohexanone proceeded
Based on the proposed transition state model
(Fig. 2),7a,b the stereochemistry of the aldol products was

3374
J.-F. Zhao et al. / Tetrahedron Letters 49 (2008) 3372–3375
easy to be explained. Similar to the reported results,3,4,5o
this reaction takes place under biphasic basic conditions
and the catalytic efficiency is somewhat dependent on the
balance between hydrophilicity and hydrophobicity of the
catalyst as well as the substrate. As shown in Table 1, cata-
lyst 1 and 4 are better than 2 and 3, respectively. This may
be due to 2 being too hydrophobic while 3 being too hydro-
philic. Proline amide 3, the best catalyst used in previous
studies,6b,7b,c bears two electron-withdrawing ester group
which strengthen the double hydrogen bonds but, unfortu-
nately, increase the hydrophilicity of the catalyst too much.
In catalyst 4, the over increased hydrophilicity was com-
pensated by the introduction of the hydrophobic siloxy
group. The relationship between hydrophobicity and cata-
lyst efficiency was also observed in the direct aldol reac-
tions of acyclic ketones. The enantioselectivity increases
as the length of alkyl chain becomes longer (Table 3, entries
3–8). The highest enantioselectivity of 89% ee was observed
for 4-phenyl-butan-2-one. This might be attributed to the
stronger hydrophobicity of the longer alkyl chain.
In summary, we have discovered highly efficient organo-
catalyzed direct aldol reactions of acyclic and cyclic
ketones with a wide range of aromatic aldehydes in water,
which afforded high yields with excellent diastereo and
enantioselectivities. The catalyst 4 is highly efficient and
as little as 1 mol % of 4 is significant to efficiently catalyze
the direct aldol reaction in water. Apparently, the current
water-compatible aldol reaction tolerates a wide scope of
donors, which will enhance its utility in organic synthesis.
What is more, highly efficient asymmetric direct stoichio-
metric aldol reactions can be realized in water, which
makes this protocol atom-economical and ‘green’.
Table 3
trans-4-Hydroxy-prolinamide 4 catalyzed direct aldol reactions of 6a with
various ketones in watera
O
OH
O
O
4
1 mol %
H2O, 25
H
+
R1 R2
º
C
R1 R2
7aa-ha
O2N
O2N
5a-h
6a
Entry Product
Time Yieldb drc
eed
(h)
(%)
(anti:syn) (%)
OH
OH
O
1
5
99
>99:1
90:10
94
95
(7aa)
O2N
O
(7ba)
(7ca)
2
70
75
O2N
O
O
OH
O
3
14
12
85
30
—
—
71
78
O2N
OH
O
4e
(7da)
O2N
OH
OH
O
5f
35
24
75
62
80
88
—
—
—
—
85
84
85
89
(7ea)
O2N
O
6f
7fa
(
)
O2N
Acknowledgement
OH
O
7f
24
We are grateful for the financial support from National
Natural Science Foundation of China (Projects 20472082,
203900505 and 20325211).
(7ga)
O2N
OH
O
8f
Ph 70
References and notes
7ha
(
)
O2N
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Rev. 2002, 102, 2751; (c) Kobayashi, S.; Manabe, K. Acc. Chem. Res.
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a
See Ref. 8.
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral-phase HPLC analysis.
Other isomer amount is of 25%.
b
c
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d
e
f
Only one of the regio-selective isomers was observed.
CO2Et
CO2Et
O
TBSO
N
O
N
H
H
O
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Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958.
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H
R
Fig. 2. Proposed transition state model.

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8. General procedure for prolinamide 4-catalyzed aldol reaction in water:
To a mixture of prolinamide 4 (0.005 mmol) in water (0.5 mL), ketone
(1.0 mmol) and aldehyde (0.5 mmol) were added at 25 °C under air.
The reaction mixture was vigorously stirred for the indicated time.
Then 10 mL saturated ammonium chloride was added. The reaction
mixture was extracted with ethyl acetate, dried over anhydrous
MgSO4. After the removal of the solvent, the residue was purified
through flash column chromatography on a silica gel to give the
corresponding aldol products.