Highly efficient and solvent-free direct aldol reaction catalyzed by glucosamine-derived prolinamide

Article abstract of DOI:10.1016/j.tetasy.2010.06.009

The catalytic activity of novel sugar-based prolinamides in the aldol reaction between ketones and aryl aldehydes has been examined. The prolinamide 1c was found to be an efficient organocatalyst for the asymmetric aldol reaction under solvent-free condit

Full text of DOI:10.1016/j.tetasy.2010.06.009

Tetrahedron: Asymmetry 21 (2010) 1906–1909
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly efficient and solvent-free direct aldol reaction catalyzed
by glucosamine-derived prolinamide
*
Jyoti Agarwal, Rama Krishna Peddinti
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic activity of novel sugar-based prolinamides in the aldol reaction between ketones and aryl
aldehydes has been examined. The prolinamide 1c was found to be an efficient organocatalyst for the
asymmetric aldol reaction under solvent-free conditions. A variety of ketones and aldehydes were used
as substrates and the corresponding aldol products were obtained in excellent chemical yields with high
levels of anti diastereoselectivity (up to 99:1) and enantioselectivity (up to >99%).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 April 2010
Accepted 3 June 2010
Available online 12 August 2010
1. Introduction
OBn
OBn
O
O
Asymmetric organocatalysis has attracted a great deal of atten-
tion by scientists worldwide due to its wide applicability in various
organic transformations.1–3 After the pioneering work reported by
List, Barbas and Lerner which proves proline as an active and ver-
satile organocatalyst in the asymmetric aldol reaction,4 numerous
organocatalysts have been designed for this reaction. In recent
years, prolinamides have been established as another class of
organocatalysts for the direct asymmetric aldol reaction.5,6
Although the introduction of an amide linkage provides more
opportunity to perform reactions in various organic solvents, some
drawbacks such as longer reaction times and low selectivities are
associated with prolinamide catalysis.
BnO
BnO
BnO
BnO
HN
HN
OMe
O
OBn
O
H
N
H
N
1c
1a
OR
O
RO
RO
HN
R =
To the best of our knowledge, only one report is published using
OMe
O
sugar-based prolinamides as organocatalyst.7 Machinami et al.
H
N
have employed methyl 2-deoxy-2-(L-prolyl)amido-a-D-glucopy-
ranoside as an organocatalyst for the direct asymmetric aldol reac-
tion between acetone and 4-nitrobenzaldehyde in water as a
solvent and they obtained the corresponding aldol adduct in mod-
erate yield and enantioselectivity. The generality of this sugar-
based organocatalyst is not known and the improvement of both
yield and asymmetric induction for the reported example is still
required.
Our laboratory has taken a long-term goal of developing novel
chiral catalysts for asymmetric synthesis.8 In this context, we have
developed a sugar-based prolinamide bearing two stereogenic
structural motifs in the same molecule with an amide linkage
(Fig. 1). We reasoned that hydrogen bonding between the amide
proton and carbonyl group of the aldehyde and effective blocking
1b
Figure 1. Structures of sugar-based prolinamides.
of one face of the aldehyde with the substituted sugar moiety bear-
ing an
a-alkyloxy group at the anomeric position would result in
an asymmetric induction. At the same time the presence of benzyl
groups on the sugar moiety improves its solubility in the reaction
medium which may lead to an enhancement in the rate of reaction.
2. Results and discussion
Herein we report sugar-based novel prolinamide-catalyzed
highly diastereoselective and enantioselective aldol reactions
in solvent-free conditions. Initially, we investigated the direct
* Corresponding author. Tel.: +91 13 3228 5438; fax: +91 13 3227 3560.
E-mail addresses: rkpedfcy@iitr.ernet.in, ramakpeddinti@rediffmail.com (R.K.
Peddinti).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.009

J. Agarwal, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 1906–1909
1907
Table 2
intermolecular aldol reaction between 3-nitrobenzaldehyde 2b
and cyclohexanone using catalyst 1a. Several polar and nonpolar
solvents have been screened at room temperature. To our surprise,
the best results were obtained in neat conditions when the reac-
tion was performed with 15 equiv of ketone. The reaction was
completed within 3 h with an excellent chemical yield and a good
enantioselectivity (Table 1, entry 7). To improve the enantiomeric
excess of the reaction, the benzyl groups of the catalyst 1b were re-
placed with bulky p-tert-butylbenzyl groups. However, no
improvement in enantioselectivity was observed (Table 1, entry
9). At this juncture, the anomeric methoxy group of 1a was re-
placed with a benzyloxy group and the aldol reaction was carried
out between cyclohexanone and 3-nitrobenzaldehyde at room
temperature. Gratifyingly, the prolinamide 1c-catalyzed aldol reac-
tion provided the adduct 3b with an excellent chemical yield and
high enantioselectivity. The asymmetric induction was further im-
proved by conducting the reaction at 0 °C under neat conditions
using 20 mol % catalyst loading (Table 1, entry 12).
Aldol reaction of cyclic ketones with substituted benzaldehydes in the presence of 1ca
O
O
O
OH
Catalyst 1c
+
R
R
º
0 C
X
X
2
3-6
X = CH2, O, S, -
S. No.
X
R
Product Time (h) Yieldb (%) anti:sync eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15e
16e
17
18
19
20
21
CH2 o-NO2
3a
3b
3c
3d
3e
3f
3g
3h
3i
5
5
5
97
96
98
85
89
91
82
97
99
91
86
87
96
95
89
92
98
94
98
89
87
97:3
91:9
93:7
97:3
91:9
98:2
91:9
90:10
71:29
99:1
97:3
77:23
94:6
95:5
98:2
94:6
96
93
91
97
97
96
>99
91
94
99
99
98
97
84
97
95
CH2 m-NO2
CH2 p-NO2
CH2 o-Br
CH2 p-Br
CH2 o-Cl
CH2 p-Cl
CH2 p-CN
CH2 p-F
21
16
20
20
10
9
21
25
26
7
CH2 1-Naphthyl 3j
CH2 o-OMe
CH2 p-OMe
3k
3l
O
O
S
o-NO2
p-NO2
o-NO2
p-NO2
o-NO2
m-NO2
p-NO2
o-Br
4a
4b
5a
5b
6a
6b
6c
6d
6e
Table 1
6
Optimization conditions for the aldol reactiona
48
48
7
8
7
S
—
—
—
—
—
48:52
28:72
18:82
51:49
38:62
>99 (82)f
89 (86)f
86 (85)f
83 (94)f
>99 (83)f
O
O
OH
O
Catalyst
Solvent
NO2
NO2
+
16
16
p-Br
2b
Entry Catalyst Solvent
3b
a
Reactions were performed with cyclic ketone (0.3 mL) and an aryl aldehyde
(0.2 mM) in the presence of organocatalyst 1c.
b
Time
(h)
Yieldb
(%)
drc
anti:syn anti: syn
eed (%)
Pure and column chromatographically isolated yields.
c
Determined by 1H NMR of the crude sample.
d
Ee of anti products determined by HPLC analysis.
Reaction was performed with ketone (0.4 mM) and aryl aldehyde (0.2 mM) in
e
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
MeOH
CH2Cl2
CHCl3
DMSO
H2O
96
96
96
96
7
90
94
90
82
95
92
65:35
67:33
70:30
58:42
54:46
60:40
27
46
43
61
27
30
23
38
33
12
22
24
the presence of organocatalyst 1c in 0.5 mL of CH2Cl2.
f
In parenthesis, ee of syn product is given.
DMSO/H2O
4:1
96
adducts 3d–g with excellent enantioselectivities (Table 2, entries
4–7). The reaction of 4-fluorobenzaldehyde was relatively faster
than those of other halo-benzaldehydes, and the fluoro-adduct
3i was obtained in excellent enantiomeric excess with diminished
diastereoselectivity (Table 2, entry 9). The product 3h with p-cy-
ano-substitution was obtained in comparable selectivities as
those of aldol adduct 3c bearing p-nitro-substitution. It is worth
mentioning here that though the reactions of 1-naphthyl alde-
hyde and methoxybenzaldehydes were slow, the corresponding
adducts 3j–l were obtained in almost enantiomerically pure form
(Table 2, entries 10–12). Other cyclic ketones such as tetrahydro-
pyran-4-one and tetrahydrothiopyran-4-one have also been used
as aldol donors. These reactions afforded the products 4 and 5
in high to excellent diastereoselectivities and enantioselectivities.
We observed that the reaction times are significantly increased in
instances where the reactions are performed in solvent for the
solid ketone tetrahydrothiopyran-4-one (Table 2, entries 15 and
16).
Encouraged by the results obtained with six-membered cyclic
ketones, we next probed the aldol reaction between aryl alde-
hydes and cyclopentanone using catalyst 1c. The results are sum-
marized in Table 2. Although the diastereoselectivities are not
impressive, both the syn and anti products were obtained in very
high enantioselectivities. The acyclic ketone acetone also worked
well in the reactions with the tested aromatic aldehydes. These
reactions afforded the desired aldol products 7a–c in 7–14 h in
high yields with no dehydration products being isolated. The
asymmetric induction in these reactions is better in comparison
with those catalyzed by proline 84a or sugar-based prolinamide
97 (Table 3).
7
8e
9
1a
1a
1b
1b
1c
1c
Neat
Neat
Neat
Neat
Neat
Neat
3
7
4
7
3
5
98
97
91
89
97
96
80:20
90:10
82:18
91:9
90:10
91:9
69
72
68
74
88
93
26
—
—
—
—
—
10e
11
12e
a
Reactions were performed with cyclohexanone (0.4 mM) and 3-nitrobenzal-
dehyde (0.2 mM) in the presence of organocatalyst 1 (0.04 mM) in 0.5 mL of solvent
in entries 1–6; cyclohexanone (0.3 mL) and 3-nitrobenzaldehyde (0.2 mM) were
used in entries 7–12.
b
Pure and column chromatographically isolated yields.
Determined by 1H NMR of the crude sample.
c
d
Determined by HPLC analysis (Chiralpak OD-H).
Reaction was performed at 0 °C.
e
To evaluate the substrate scope for this reaction, several
aromatic aldehydes with diversified substituents were tested in
the presence of 20 mol % organocatalyst 1c. Numerous electron-
rich and electron-deficient aldehydes with different substitution
patterns gave rise to products 3a–l in high yields and with high
levels of diastereo- and enantioselectivity (Table 2). In all cases,
anti aldol products were obtained with high enantioselectivity
and diastereoslectivity and the rate of reactions depends upon
the position and nature of the substitution on the aromatic moi-
ety. The reactions of cyclohexanone with nitrobenzaldehydes
were faster irrespective of the position of the nitro functionality
and afforded the corresponding aldol adducts 3a–c in good diaste-
reoselectivity and enantioselectivity (Table 2, entries 1–3). The
halo-benzaldehydes participated in the aldol reaction to provide

1908
J. Agarwal, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 1906–1909
Table 3
Aldol reaction of acetone with substituted benzaldehydesa
O
O
OH
O
Catalyst
R
R
+
2
7
OBn
OH
O
O
BnO
BnO
HO
HO
HN
COOH
HN
OBn
O
N
OMe
O
H
N
H
H
N
1c
8
9
Entry
Catalyst (mol %)
Product
Solvent
Yield (%)
ee (%)
1
2
1c (20)
8 (30)
—
DMSO
98
68
95
76
O
OH
3
9 (30)
Water–acetone
61
69
NO2
Br
4
5
1c (20)
8 (30)
—
DMSO
86
74
93
65
O
O
OH
6
7
1c (20)
8 (30)
—
DMSO
96
94
94
69
OH Cl
a
Reactions catalyzed by 1c were carried out at 0 °C, while the other reactions were performed at room temperature.
repulsions and the enantioselective C–C bond formation takes
place on the re-face of the aldehyde leading to the production of
the (1R,2S)-isomer.
H
H
BnO
BnO
BnO
BnO
OBn
OBn
H
O
H
O
H
H
H
H
O
O
N
N
3. Conclusion
O
O
H
H
H
H
N
N
O
In conclusion, we have demonstrated a mild and facile meth-
od for catalytic enantioselective aldol reaction between ketones
O
H
and aromatic aldehydes using
a sugar-derived prolinamide
H
under solvent-free conditions. Currently we are exploring the
applicability of the title organocatalyst in other catalytic
transformations.
TS1
TS2
4. Experimental
Figure 2. Plausible transition state.
4.1. Typical procedure for the enantioselective aldol reaction
catalyzed by organocatalyst 1c
To account for the stereochemical outcome of the current study,
we propose that sugar-based prolinamide catalyst 1c could cata-
lyze the direct aldol reaction via the plausible transition state
TS1 shown in Figure 2. The aldehyde could be activated by hydro-
gen bonding with NH at C-2 of glycon unit of the catalyst as shown
in TS1 and TS2. The TS2 leading to the (1S,2S)-isomer is unfavoured
since the approach of the aldehyde in the orientation shown is ob-
structed by the bulky a-benzyloxy group at the anomeric carbon of
the sugar moiety on the catalyst framework. Consequently, the ap-
proach of the aldehyde in TS1 is facile since there are no such steric
A
solution of aldehyde (0.2 mmol), organocatalyst 1c
(0.04 mmol, 20 mol %) and cycloalkanone (3 mmol) was stirred
for 5–48 h at 0 °C. The reaction was monitored by TLC at regular
intervals. Upon completion of the reaction, the crude product
was submitted for 1H NMR (500 MHz) to determine the diastereo-
meric excess. The residue was subjected to column chromatogra-
phy on silica gel to afford a pure product. The HPLC analysis of
the aldol product was performed on a chiral stationary phase using
hexane–isopropanol as eluting solvent.

J. Agarwal, R. K. Peddinti / Tetrahedron: Asymmetry 21 (2010) 1906–1909
1909
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