Direct asymmetric aldol reaction catalyzed by C2-Symmetrical chiral primary amine organocatalysts

Article abstract of DOI:10.2174/157017810790533904

Three novel C₂-symmetrical chiral primary amines were synthesized from chiral BINOL and diamines. Then their catalytic activities in the asymmetric aldol reactions were evaluated, and the result indicated that 1c was the optimal organocatalyst.

Full text of DOI:10.2174/157017810790533904

Letters in Organic Chemistry, 2010, 7, 15-20
15
Direct Asymmetric Aldol Reaction Catalyzed by C -Symmetrical Chiral
2
Primary Amine Organocatalysts
Gong-Jian Zhu, Chao-Shan Da*, Ya-Ning Jia, Xiao Ma and Lei Yi
Institute of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
Received September 09, 2009: Revised October 30, 2009: Accepted November 16, 2009
2
Abstract: Three novel C -symmetrical chiral primary amines were synthesized from chiral BINOL and diamines. Then
their catalytic activities in the asymmetric aldol reactions were evaluated, and the result indicated that 1c was the optimal
organocatalyst. The reaction of a variety of aromatic aldehydes with aliphatic ketones, catalyzed by 20 mol % 1c in the
addition of benzoic acid in carbon tetrachloride, afforded the aldol products in high yields (up to 92%) and good
enantioselectivities (up to 71%).
2
Keywords: Aldol reaction, asymmetric organocatalysis, chiral primary amine, C -symmetry, benzoic acid.
1
. INTRODUCTION
to the synthetic route shown in Scheme 1. The hydroxyl
groups of 2 were protected as methoxymethyl (MOM) ethers
The aldol reaction has long been recognized as one of the
[
4]. The resulting 3 was subjected to ortho-lithiation [13],
most fundamental tools for the construction of new carbon-
carbon bonds [1]. Inspired by the exquisite stereocontrol in
the enzymatic enamine processes, chemists have long been
pursuing a simple chemical mimic for asymmetric enamine
catalysis, and this aim has now been partially fulfilled with
the renaissance of organocatalysis [2]. However, the most
successful enamine organocatalysts mainly utilize secondary
amines instead (e.g. chiral pyrrolidine derivatives) at present
followed by carboxylation to give the corresponding 3,3'-
dicarboxylic acid (4). The diacid chlorides, which was
readily prepared by exposure of diacid (4) to thionyl
chloride, was successively treated with mono-Boc protected
diamines (5) and then directly with TFA to give the
corresponding
2
C -symmetrical primary amine organo-
catalysts 1a-b. When (S)-BINOL was used to be the starting
reagent instead of (R)-BINOL, 1c was achieved according to
the same synthetic procedure as 1a-b in the end.
[
3, 4]. In this context, exploration of efficient and stereo-
selective primary amine catalysts has become a much-
attempted research endeavor [5]. Recently, simple primary
amino acids and simple peptides having a N-primary amino
group were found to act as effective catalysts for the direct
asymmetric aldol reactions [6-9]. And we [10, 11] and other
groups [12] have successfully demonstrated the effectiveness
of chiral primary amine catalysts for the highly
enantioselective aldol reactions for a broad spectrum of
ketones. Although remarkable progress in effective chiral
primary amine catalysts has been made in the past few years,
new strategies regarding the design of novel primary amine
catalysts with high efficiency and high stereoselectivity
Initially, the asymmetric catalytic activities of 1a-c were
tested in the model reaction of 4-nitrobenzaldehyde with
acetone in the presence of 10 mol% catalyst at room
temperature. The best catalytic efficiency was observed with
1c (Table 1, entry 4). Compounds 1a-b exhibited lower
catalytic activity and enantioselectivity (entries 5 and 6). As
can be seen, 20 mol% acidic additive TFA (trifluoroacetic
acid) was shown to be essential for effective catalysis. The
reaction was very sluggish, affording only trace product if
TFA was absent (Table 1, entries 1-3). Both catalysts 1a and
1b could catalyze the reaction jointly with TFA, while 1c
gave the optimal results (Table 1, entry 4). In comparison of
1a with 1c, both of them achieved the (R)-aldols. Therefore,
it could be concluded that the asymmetric sense was
determined by the chiral diamine moiety instead of the
BINOL scaffold, and the catalyst 1c from (S)-BINOL and
(1S,2S)-cyclohexanediamine is the superior combination to
1a from (R)-BINOL and the same diamine.
remains
a
challenge. Furthermore, primary amine
-symmetry have not been
organocatalysts with structural C
2
disclosed in this transformation to date. This is a more
interesting and greatly desired topic. Herein, we first report
the preparation of three novel C -symmetrical chiral
2
organocatalysts from the chiral BINOL and diamines and
their effective application in aldol reaction.
In order to further improve enantioselectivity, a series of
acid additives were screened in the same model aldol
reaction. These subsequent investigations revealed that
benzoic acid served as the best additive, which was able to
2
. RESULTS AND DISCUSSION
-symmetrical primary amines (1a-c) were prepared
C
2
from commercially available starting materials (R)-BINOL
and corresponding Boc-protected chiral diamines according
increase the enantioselectivity to 38% ee within
a
comparably short reaction time in comparison with TFA and
other acidic additives (Table 1, entry 9). With these results in
mind, we next tried to evaluate the catalyst loading and the
solvents. A notable improvement on the enantioselectivity
was obtained when the catalyst loading changed from 10
*
Address correspondence to this author at the Institute of Biochemistry &
Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou
30000, China; Fax: +86-931-8915208; E-mail: dachaoshan@lzu.edu.cn
7
1
570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

1
6
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Zhu et al.
i. HCl
ii. (Boc) O
2
R
N
R
R
R
5
5
a: 2R= -(CH
b: R= Ph
2 4
) -
iii. NaOH
H
2
NH
2
HN
NH2
Boc
5
a-b
COOH
i. n-BuLi
ii. CO
OH
OH
OMOM
OMOM
OMOM
i. NaH
ii. MOMCl
2
iii. HCl
OMOM
COOH
2
2
3
4
H
2
N
H N
H N
Ph
Ph
2
HN
HN
HN
O
O
O
i. SOCl
2
ii. 5
OMOM
OMOM
OMOM
OMOM
or
or
OMOM
O
OMOM
iii. TFA
O
O
HN
HN
HN
Ph
Ph
1a
1b
1c
H
2
N
H N
2
H N
2
Scheme 1. Synthesis of catalysts 1a-c.
Table 1. Screening of the Catalysts and Acidic Additives
O
OH
CHO
O
1c (10 mol%)
+
Add. (x mol%), rt
O N
2
NO
2
a
b
c
Entry
Catalyst
Additive
Time (h)
Yield(%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1b
1a
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
none
none
none
>144
>144
>144
120
120
120
72
<5
<5
<5
51
ꢀ
ꢀ
ꢀ
30
18
25
7
TFA (20)
TFA (20)
TFA (20)
DNP (20)
46
45
33
CH
3
COOH (20)
COOH (20)
HCOOH (20)
CCl COOH (20)
TsOH (20)
COOH (5)
COOH (10)
72
64
27
38
ꢀ
ꢀ
20
12
27
37
38
C
6
H
5
60
75
1
1
1
1
1
1
1
0
1
2
3
4
5
6
120
120
120
96
trace
trace
35
3
C
6
H
5
49
C
6
C
6
C
6
H
H
H
5
5
5
75
63
COOH (15)
COOH (30)
68
76
60
75
a
Data in the parenthesis is the amount of the additive.
Isolated yields.
b
c
The ee values were determined by chiral HPLC on a AS-H column. The configuration was determined by the HPLC retention time or the sign of the optical rotation with the
literature data [10a].

Direct Asymmetric Aldol Reaction Catalyzed
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
17
mol% to 20 mol%. However, further improvement was not
obtained when the catalyst loading increased to 30 mol%;
enamines, which were formed by the primary amines with
acetone, would mainly attack the aldehyde from its Re face
to predominantly afford the R-configuration aldol Fig. (1).
therefore 20 mol% was the preferred loading. CCl
found superior over more polar solvents (Table 2, entries 9-
1). Under the optimized conditions, enantioselectivities of
4
was
In conclusion, starting from commercially available
chiral BINOL and diamines, three novel C -symmetrical
2
1
the other two catalysts were rechecked and 1c was still
chiral primary amine organocatalysts were readily prepared
and then they were employed to catalyze the asymmetric
aldol reactions of ketones and aromatic aldehydes. It was
found that acidic additive contributed to high activity and
enantioselectivity of 1c; benzoic acid was the most
optimized additive. In the addition of 20% benzoic acid, 1c
could successfully catalyze the reaction of several aliphatic
ketones with aromatic aldehydes with high yields and
moderate to good enantioselectivities.
revealed to exhibit the highest level of enantioselectivity
(
Table 2, entries 12-13).
A number of aldol reactions were carried out under the
optimized reaction conditions described above in the
presence of 20 mol% 1c in CCl . Examination of the results
4
revealed that aldol processes promoted by 1c were generally
applicable to various aryl aldehyde acceptors (Table 3,
entries 1-11). The 3-nitro and 4-nitrobenzaldehyde afforded
very similar yields and enantioselectivities in the reaction
with acetone. It was worth noting that the reaction of
butanone with 4-nitrobenzaldehyde yielded the aldol product
with the highest 71% ee (Table 3, entry 12). Surprisingly, the
reaction of cyclopentanone with aromatic aldehydes
displayed high yields but moderate enantioselectivities
3
. EXPERIMENTAL SECTION
General
All chemicals were used as received unless otherwise
noted. Reagent grade solvents were dried and distilled prior
(
Table 3, entries 13-14). In general, the higher
1
to use. All reported H NMR spectra were collected on a
enantioselectivities were obtained with aldehydes carrying
strong electron-withdrawing groups. Most of the halo-
substituted benzaldehydes furnished the corresponding aldol
products in high yields with good enantioselectivities (Table
Bruker AM-400 NMR and DRX-200 spectrometer with
TMS as the internal reference. IR spectra were determined
on a Nicolet Magna 550 instrument. High resolution mass
spectra (HR-MS) were obtained on a Bruker APEX II
instrument using the ESI technique. Chromatography was
performed on silica gel (200–300 mesh). Melting points
were determined using an X-4 apparatus. Optical rotations
were determined on VtrZZ-I polarimeter. Enantiomeric
excess was measured by a Waters 600 HPLC equipped with
3
, entries 6-8). When aliphatic aldehydes were used as
substrates, no aldols were yielded.
Based on the disclosed speculations on the reactive
mechanism of this transformation [8], transition state model
analog was proposed in order to clarify the sense of the
asymmetric induction of the catalyst 1c. Both the amides and
the hydroxy groups of the phenols would be probably
hydrogen-bonded with the aldehyde to activate it. And the
2
996 UV detector with Chiralpak AD-H, Chiralcel OJ-H or
Chiralcel AS-H column.
a
Table 2. Optimization of the Solvents and the Loading of the Catalyst 1c
b
c
d
Entry
Catalyst
Solvent
Time (h)
Yield(%)
ee (%)
1
2
3
4
5
6
7
8
9
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (10)
1c (20)
1c (30)
1a (20)
1b (20)
DMF
EtOH
MeOH
THF
120
80
120
72
80
96
84
84
40
28
28
30
36
14
50
<5
45
46
60
71
70
86
91
90
83
82
5
51
23
25
37
47
54
50
52
61
58
56
53
toluene
xylene
CH
2
Cl
2
CHCl
3
CCl
CCl
CCl
CCl
CCl
4
4
4
4
4
1
1
1
1
0
1
2
3
a
The reactions were performed under room temperature and 20% benzoic acid were added.
Data in the parenthesis is the amount of the catalyst.
Isolated yields.
b
c
d
The ee values were determined by chiral HPLC on a AS-H column. The configuration was determined by the HPLC retention time or the sign of the optical rotation with the
literature data [10a].

1
8
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Zhu et al.
Table 3. Asymmetric Aldol Reactions of Ketones with Aromatic Aldehyde Catalyzed by 1c
O
catalyst 1c (20 mol%)
O
OH
CHO
benzoic acid (40 mol%)
+
R
R
R1
R2
CCl , rt
R1
R2
4
a
b
c
Entry
R
1
R
2
R
Time (h)
Yield (%)
Anti/syn
ee (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
4-NO
3-NO
2-NO
2
2
2
26
28
28
96
96
55
96
48
48
65
66
72
24
20
48
92
82
82
25
57
61
91
65
88
44
83
87
90
91
80
ꢀ
ꢀ
61
63
50
59
51
57
60
45
59
49
56
71
55
36
66
H
H
ꢀ
H
2-OCH
3-OCH
2-Cl
3
3
ꢀ
H
ꢀ
H
ꢀ
H
3-Cl
ꢀ
H
2-Br
ꢀ
H
2-CF
3
ꢀ
1
1
1
1
1
1
0
1
2
3
4
5
H
1-Napthyl
2-Napthyl
ꢀ
H
ꢀ
CH
3
4-NO
2-NO
4-NO
4-NO
2
2
2
2
1/1
1/1
1/2
1/3
(-CH
(-CH
2
2
-)
-)
2
2
CH
3
CH
3
a
Isolated yields.
Determined by chiral HPLC.
b
c
Determined by chiral HPLC. The configuration was assigned was determined by the HPLC retention time or the sign of the optical rotation with the literature data. And the anti/syn
1
was determined by H NMR [10a].
O
N
H
N
H
H
O
O
O
H
O
Ar
Ar
O
OH
O
H
N
Ar
H
H
N
H
Fig. (1). Proposed transition state model.
General Procedure for the Preparation of mono-Boc
Protection Of Diamine (5) [14]
carefully added into (1S,2S)-cyclohexanediamine (4.66
mmol) at 0 C. The mixture was slowly warmed to room
temperature and stirred for another 15 min before adding 5
o
o
To 150 mL cool MeOH at 0 C, dry gaseous HCl (1.7 g)
mL H
10.1 g, 4.66 mmol) in 20 mL MeOH was added dropwise at
room temperature for 15 min, and the resulted solution was
2 2
O and stiring further 0.5 h. Then the solution (Boc) O
was slowly bubbled into with stirring for 15 min. The
mixture was stirred for 15 min at room temperature and then
(

Direct Asymmetric Aldol Reaction Catalyzed
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
19
stirred for 1h. The mixture was concentrated to dryness in
vacuo and the unreacted diamine was removed by washing
with the diethyl ether (30 mL) two times. The residue was
66%). This material was used for the next step without
o
18
further purification. Mp > 290 C; [ꢀ]
D
-187 (c 1.1,
1
pyridine); H NMR (400 MHz, acetone-d
6
) ꢀ: 10.99 (s, 2H),
treated with 2 N NaOH (50 mL) and extracted with CH
30 mL) three times. The combined organic extracts were
washed with saturated brine, dried with Na SO , condensed
in vacuo to afford the mono protected diamine, which was
recrystallized from methanol-dichloromethane to furnish 5a
as a white crystal.
2
Cl
2
8.81 (s, 2H), 8.08 (m, 2H), 7.38 (m, 6H), 7.13 (s, 2H).
(
General Procedure for the Preparation of
symmetrical primary diamine organocatalysts (1)
2
C -
2
4
A solution of the dicarboxylic acid 3 (0.822 g, 2.2 mmol)
in thionyl chloride (10 mL) was refluxed for 4 h. After
removal of thionyl chloride by distillation under reduced
(
(
1S,2S)-2-Aminocyclohexylcarbamic acid tert-butyl ester
5a)
pressure, the resulted acid chloride was dissolved in CH
2 2
Cl
(
5 mL). The mixture was added to a stirred solution of 5 (4.0
o
1
White crystal: yield 78%; mp 114-115 C; H NMR (200
MHz, CDCl ) ꢀ 4.50 (m, 1H), 3.12 (m, 1H), 1.90 (m, 2H),
.68 (m, 2H), 1.45 (s, 9H), 1.26 (m, 4H).
mmol) and triethylamine (1.6 mL, 12 mmol) in
o
3
dichloromethane (40 mL) at 0 C. After stirred for 4 h at
1
room temperature, the mixture was acidified to pH 2 with
5
% aqueous HCl and extracted with dichloromethane two
times. The combined organic layers were washed with brine,
dried over Na SO , and concentrated in vacuo. Then the
(
1R, 2R)-2-Amino-1,2-diphenylcarbamic acid tert-butyl
ester (5b)
2
4
o
1
Yellow power: yield 80%; mp 102-103 C; H NMR (200
MHz, CDCl ) ꢀ 7.22-7.38 (m, 10H), 5.78 (d, 1H), 4.34 (d,
H), 1.28 (s, 9H).
residue was purified on silica gel (petroleum ether /ethyl
acetate = 4:1, v/v) to give a yellow solid product.
Deprotection of the Boc group was performed by using TFA
for 2 h at room temperature. After evaporation of TFA, the
3
1
residue was basified to pH 8 with 5% aqueous NaHCO
extracted with dichloromethane three times. The combined
organic layers were washed with brine, dried over Na SO
2 4
and concentrated to give the catalyst 1 as a yellow solid.
3
and
General Procedure for the Preparation of (R)-2,2ꢀ-
Bis(methoxymethoxy)-1,1ꢀ-binapthyl (3) [4]
To a solution of NaH (60% dispersion in mineral oil,
1
.84 g, 46 mmol) in a solution of dry 80 mL THF and 40 mL
N,Nꢀ-Bis[(1S,2S)-(2-amino)]cyclohexyl-(R)-2,2ꢀ-dihydroxy-
1,1ꢀ-binaphthyl-3,3ꢀ-dicarboxamide (1a)
DMF was added dropwise a solution of 5.90 g (R)-BINOL 2
o
(
20.6 mmol) in 24 mL dry THF at 0 C. After stirring for 1 h
at room temperature, 6.0 mL chloromethyl methyl ether
MOMCl, 65 mmol) was introduced to the resultant mixture.
o
20
D
Yellow powder, 498 mg, yield 88%; mp > 300 C; [ꢁ] =
-
1
(
–117 (c 1.0, DMSO), IR (KBr, cm ): 3349, 3321, 1643,
1
A white precipitate immediately appeared and the reaction
was further stirred for 4 h at room temperature. Then the
reaction was quenched with cold water. Extracted the
mixture with ethyl acetate three times, combined the organic
1619; H NMR (400 MHz, CDCl
3
) ꢀ: 8.41 (s, 2H), 7.95 (d,
2H), 7.25-7.50 (m, 28H), 5.49 (d, 2H), 4.91 (d, 2H), 1.90-
1
3
2.08 (m, 2H); C NMR （200 MHz, CDCl ）ꢀ: 167.4,
3
158.2, 135.5, 130.1, 129.2, 126.5, 125.6, 125.0, 122.0, 121.6,
119.1, 53.7, 52.1, 40.6, 40.2, 39.8, 39.4, 39.0, 38.5, 38.1,
2 4
layers, washed with little saturated brine, dried with Na SO ,
condensed in vacuo. The resultant residue was recrystallized
with methanol to give the aimed product as a white crystal.
31.5, 31.2, 24.3, 23.6; HR- MS: cacld for C34
H) 567.2966, found 567.2976.
H
38
N
4
O
4
(M +
+
o
20
7
.2 g, yield 94%; mp 103–104 C; [ꢀ]
D
+98 (c 0.9, THF);
) ꢀ 7.95 (d, J = 9.2 Hz, 2H), 7.87
d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 8.0
Hz, 2H), 7.25–7.20 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 5.09
d, J = 6.8 Hz, 2H), 4.97 (d, J = 6.8 Hz, 2H), 3.14 (s, 6H).
1
N,Nꢀ-Bis[(1R,2R)-(2-amino)]diphenyl-(R)-2,2ꢀ-dihydroxy-
H NMR (400 MHz, CDCl
3
1
,1ꢀ-binaphthyl-3,3ꢀ-dicarboxamide (1b)
(
o
20
Yellow powder, 543 mg, yield 89%; mp > 300 C; [ꢁ] =
D
-
1
1
(
+ 26 (c 2.0, CHCl
NMR (400 MHz, CDCl
3
), IR (KBr, cm ): 3379, 1647, 1619; H
) ꢀ: 8.49 ( s, 2H), 7.83-7.86 (d, 2H),
.83-7.11 (m, 4H), 6.76-6.78 (d, 2H), 5.15-5.27 (br, 2H),
.69-2.71 (m, 2H) 1.90-2.08 (m, 2H), 1.19-1.45 (m, 16H);
3
6
2
General Procedure for the Preparation of (R)-2,2ꢀ-
dihydroxy-1,1ꢀ-binapthyl-3,3ꢀ- dicarboxylic acid (4)
13
C NMR (400 MHz, CDCl
3
) ꢀ: 169.2, 154.3, 141.5, 140.2,
To a solution of 3 (3 g, 8.01 mmol) in dry THF (40 mL)
141.5, 140.2, 136.2, 24.7, 123.7, 117.4, 117.0, 77.3, 77.0,
o
+
was added n-BuLi (15.3 mL, 24.0 mmol) at 0 C, dry CO
2
76.67, 59.6, 58.6; HR- MS: cacld for C50
763.3279, found 763.3270.
42 4 4
H N O (M + H)
was carefully bubbled until completion of the reaction
monitored by TLC. The aqueous layer was washed by ether
and then acidified to pH 2.0 with 5% aqueous HCl. The
acidic aqueous layer was extracted with ethyl acetate. The
combined organic phase was washed with water, saturated
N,Nꢀ-Bis[(1S,2S)-(2-amino)]cyclohexyl-(S)-2,2ꢀ-dihydroxy-
1
,1ꢀ-binaphthyl-3,3ꢀ-dicarbox -amide (1c)
o
20
Yellow powder, 498mg, yield 88%; mp > 300 C; [ꢁ] =
D
-
1
+
266 (c 2.0, DMSO ), IR (KBr, cm ): 3349, 3321, 1643,
3
) ꢀ: 8.59 ( s, 2H), 7.86 (d,
H), 7.08 (m, 4H), 6.79 (d, 2H), 3.72-4.23 (m, 2H), 2.85 (m,
H) 1.95 (m, 2H), 1.01-1.65 (m, 16H); C NMR (200 MHz,
) ꢀ: 167.4, 158.2, 135.5, 130.1, 129.2, 126.5, 125.6,
25.0, 122.0, 121.6, 119.1, 53.7, 52.153, 40.6, 40.2, 39.8,
9.4, 39.0, 38.5, 38.1, 31.5, 31.2, 24.3, 23.6; HR- MS: cacld
4
brine, dried over MgSO and concentrated under reduced
1
1
2
2
619; H NMR (400 MHz, CDCl
pressure. To the crude residue in THF (10 mL) was added
saturated HCl in i-PrOH (20 mL) and this mixture was kept
for 4 h at room temperature. After removal of solvent, the
residue was partitioned into ethyl acetate and water. The
1
3
CDCl
1
3
3
organic layers was washed with water, dried over MgSO
and concentrated. The residue was triturated with CHCl to
give a yellow powder collected by filtration (1.96 g, yield
4
3
+
38 4 4
for C34H N O (M + H) 567.2966, found 567.2976.

2
0
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Zhu et al.
amines. Tetrahedron Lett., 2004, 45, 325; (c) Amedjkouh, M.
Primary amine catalyzed direct asymmetric aldol reaction assisted
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S.; Weber, A. L. Prebiotic amino acids as asymmetric catalysts.
Science, 2004, 303, 1151; (e) Davies, S. G.; Sheppard, R. L.;
Smith, A. D.; Thomson, J. E. Highly enantioselective
organocatalysis of the Hajos-Parrish-Eder-Sauer-Wiechert reaction
by the ꢁ-amino acid cispentacin. Chem. Commun., 2005, 36, 3802;
General Procedure for Asymmetric Aldol Reaction of
Ketone (Acetone, Butanone, 3-pentanone and
Cyclopentanone) with Aldehydes
In a mixture of 1c (0.02 mmol), benzoic acid (0.04
mmol) and ketone (acetone, butanone, 3-pentanone and
cyclopentanone, respectively) (1 mmol) in CCl (1 mL),
4
aldehyde (0.1 mmol) was added and then stirred at room
temperature until the reaction was completed as judged by
(
f) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Asymmetric aldol reactions
catalyzed by tryptophan in water. Chem. Commun., 2006, 26, 2801;
g) Wu, X.; Jiang, Z.; Shen, H.M.; Lu, Y. Highly efficient
(
4
TLC. Then 5.0 mL saturated aqueous NH Cl was added and
threonine-derived organocatalysts for direct asymmetric aldol
reactions in water. Adv. Synth. Catal., 2007, 349, 812; (h)
Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III.
Direct catalytic asymmetric synthesis of anti-1,2-amino alcohols
and syn-1,2-diols through organocatalytic anti-mannich and syn-
aldol Reactions. J. Am. Chem. Soc., 2007, 129, 288; (i) Hagiwara,
H.; Uda, H. Highly enantioselective claisen-type acylation and
dieckmann annulation. J. Org. Chem., 1988, 53, 2308; (j)
Tsogoeva, S. B.; Wei, S. (S)-Histidine-based dipeptides as organic
catalysts for direct asymmetric aldol reactions. Tetrahedron
Asymmetry, 2005, 16, 1947; (k) Wu, F.-C.; Da, C.-S.; Du, Z.-X.;
Guo, Q.-P.; Li, W.-P.; Yi, L.; Jia, Y.-N.; Ma, X. N-primary-amine-
terminal ꢁ-turn tetrapeptides as organocatalysts for highly
enantioselective aldol Reaction. J. Org. Chem., 2009, 74, 4812.
(a) Xu, X.-Y.; Wang, Y.-Z.; Gong, L.-Z. Design of organocatalysts
for asymmetric direct syn-aldol reactions. Org. Lett., 2007, 9, 4247;
(b) Zhu, M.-K.; Xu, X.-Y.; Gong, L.-Z. Organocatalytic
asymmetric syn-aldol reactions of aldehydes with long-chain
aliphatic ketones on water and with dihydroxyacetone in organic
solvents. Adv. Synth. Catal., 2007, 350, 1390.
the mixture was extracted with ethyl acetate three times.
Then the organic layers were combined, dried with
anhydrous Na SO , concentrated to dryness under reduced
2 4
pressure, purified by preparative TLC or column to achieve
the aldol product.
4
-Hydroxyl-4-(4-nitrophenyl)-butan-2-one [10a]
1
3
H NMR (200 MHz, CDCl ) ꢀ: 8.20 (m, 2H), 7.55 (m,
2
H), 5.26 (s, 1H ), 3.58 (bs, 1H), 2.85 (m, 2H), 2.22 (s, 3H);
HPLC: Chiralcel AS-H, hexane/i-PrOH = 70/30, flow rate
.0 mL/min, retention time: major peak 17.4 min ((R)-
[
8]
1
isomer), minor peak 23.4 min ((S)-isomer).
ACKNOWLEDGEMENT
[
[
9]
Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.; Wang, X.-L.; He, L. Highly
enantioselective direct aldol reaction catalyzed by cinchona derived
primary amines. Org. Biomol. Chem., 2007, 5, 2913.
We are grateful for the financial support from the
National Natural Science Foundation of China (NO.
10]
(a) Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu, F.-C.; Ma, X.; Jia, Y.-N.
2
0672051).
2
,4-Dinitrophenol as an effective cocatalyst: greatly improving the
activities and enantioselectivities of primary amine organocatalysts
for asymmetric aldol reactions. J. Org. Chem., 2009, 74, 2541; (b)
Ma, X.; Da, C.-S.; Yi, L.; Jia, Y.-N.; Guo, Q.-P.; Che, L.-P.; Wu,
F.-C.; Wang, J.-R.; Li, W.-P. Highly efficient primary amine
organocatalysts for the direct asymmetric aldol reaction in brine.
Tetrahedron Asymmetry, 2009, 20, 1419.
Jia, Y.-N.; Wu, F.-C.; Ma, X.; Zhu, G.-J.; Da, C.-S. Highly
efficient prolinamide-based organocatalysts for the direct
asymmetric aldol reaction in brine. Tetrahedron Lett., 2009, 50,
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