Small organic molecule catalyzed enantioselective direct aldol reaction in water

Article abstract of DOI:10.1016/j.tetasy.2006.07.016

Protonated pyrrolidine based small organic molecules have been designed and evaluated for the asymmetric direct aldol reaction in water. The designed organocatalysts are multifunctional in nature and exploit the combined effect of hydrogen bonding and hydrophobic interactions for enantioselective catalysis in water. As a result a unique direct asymmetric aldol reaction in water catalyzed by a small organic molecule having an amide linkage has been developed. The developed catalyst affords chiral β-hydroxyketones in good yields (93%) and enantioselectivities (upto 62%) in water.

Full text of DOI:10.1016/j.tetasy.2006.07.016

Tetrahedron: Asymmetry 17 (2006) 2108–2119
Small organic molecule catalyzed enantioselective
direct aldol reaction in water
Swapandeep Singh Chimni* and Dinesh Mahajan
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
Received 15 June 2006; accepted 14 July 2006
Abstract—Protonated pyrrolidine based small organic molecules have been designed and evaluated for the asymmetric direct aldol reac-
tion in water. The designed organocatalysts are multifunctional in nature and exploit the combined effect of hydrogen bonding and
hydrophobic interactions for enantioselective catalysis in water. As a result a unique direct asymmetric aldol reaction in water catalyzed
by a small organic molecule having an amide linkage has been developed. The developed catalyst affords chiral b-hydroxyketones in good
yields (93%) and enantioselectivities (upto 62%) in water.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In the organocatalytic direct aldol reaction, water, in a
small amount has been found to enhance the rate of the
proline catalyzed direct aldol reaction in organic media
but the use of excess water results in the formation of race-
mic aldol addition product.5 Janda et al.6 based on theoret-
ical studies, have proposed the active involvement of a
water molecule in proton transfer in the nornicotine cata-
lyzed aldol reaction. Thus water seems to exert an impor-
tant influence on the organocatalyzed aldol reaction. The
development of efficient, direct asymmetric organocata-
lyzed aldol reaction in water may result in the development
of synthetic methodology having the dual benefits offered
by metal free organocatalyst and water as reaction media,
favouring green synthesis.
Organic synthesis in water is a rapidly growing area of
research since it holds great promise for the future in terms
of the cheaper and less hazardous production of chemi-
cals.1 The use of water as solvent in asymmetric reactions
has not been appreciated earlier due to the fact that water
tends to inhibit the catalyst’s activity or alter the enantio-
selectivity by interrupting ionic interactions and hydrogen
bonds, which are critical for stabilizing the transition state
of the reaction. Furthermore, the non-polar organic com-
pounds are less soluble in water. However, water due to
its small size, high polarity and the three-dimensional
hydrogen bonded network system of bulk water, provides
some unique properties, which include large cohesive
energy density, a high surface tension and hydrophobic
effect.2 The pioneering studies of Breslow et al.3 and Gri-
eco4 on Diels–Alder reaction in early 1980s have shown
that reactions in water proceed with much higher rates as
well as unprecedented regioselectivities than in organic sol-
vents. The accelerating effect of water has been ascribed to
a number of factors, including the hydrophobic effect as
well as hydrogen bonding between water molecules and
reactants. These unique properties of water can be
exploited in organocatalyzed direct asymmetric aldol
reactions.
2. Results and discussion
We seek to design metal free small organic molecules with
structural diversity for catalyzing enantioselective organic
transformations in water or under physiological med-
ium.7,9 Water has been found to accelerate the pyrrolidine
catalyzed direct aldol reaction of different ketones with a
range of aromatic aldehydes. The amine catalysis of an al-
dol reaction has been shown to proceed through an enam-
ine intermediate rather than involving a competing general
base catalysis.7
*
The asymmetric version of the pyrrolidine catalyzed aldol
reaction in water can be achieved by designing pyrrolidine
Corresponding author. Tel.: +91 183 2258802x3204; fax: +91 183
2258820; e-mail: sschimni@yahoo.com
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.016

S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2109
Table 1. Direct asymmetric aldol reaction of acetone 2 and 4-nitrobenz-
aldehyde 1a catalyzed by organocatalysts 4
based catalysts capable of inducing asymmetry in the prod-
ucts. We envisaged that the introduction of an asymmetric
centre and a suitable hydrophobic unit may provide pyrrol-
idine based asymmetric organocatalysts useful for direct al-
dol reaction in water. Furthermore, it has been observed by
Spencer et al.8 that nucleophilic catalysis in water can be
enhanced by decreasing the effective base strength of the
amine catalysts, which can be done through protonation
of the amine.9
Entry
Catalyst 4
Time
3a Yielda (%)
ee (R/S)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
36 h
7 h
8 h
32 h
8.5 h
6 h
26 h
87
88
92
83
86
87
88
83
15 (R)
8 (R)
33 (R)
3 (S)
24 (R)
39 (R)
45 (R)
46 (R)
nd
g
h
i
8 h
Herein we report the evaluation of protonated chiral prolin-
amide derivatives as asymmetric organocatalysts for the
direct enantioselective aldol reaction in water. The direct
organocatalytic aldol reaction of 4-nitrobenzaldehyde 1a
(2 mmol), and acetone 2 (40 mmol) in water (3 mL)
using (S)-2-(phenylcarbamoyl)pyrrolidinium bromide 4a
10 days
10 days
10 days
nd
52
Traces
10
11
j
31 (R)
nd
k
a Isolated yields after column chromatography.
(20 mol %) as a catalyst at ambient temperature 27
1
ꢁC on continuous stirring for 36 h, affords 4-hydroxy-4-
(40-nitrophenyl)butan-2-one 3a10 as a yellow crystalline
solid, mp: 59–61 ꢁC in 87% yield and 15% ee.
B
D
A
H
N
O
O
N
Similarly the direct aldol reaction catalyzed by other
organocatalysts (Scheme 1) have been performed and are
presented in Table 1. Organocatalyst 4b derived from L-
proline and benzylamine shows high activity with a reac-
tion time of 7 h affording 3a in 88% yield and 8% ee (Table
1, entry 2). The catalyst 4a catalyzes the same reaction in
36 h (Table 1, entry 1). This difference in reaction time
can be ascribed to the small structural difference in the
two catalysts. The catalyst 4b has a –CH2– spacer between
the amide nitrogen and the phenyl ring, which imparts flex-
ibility whereas catalyst 4a has a comparatively rigid
structure.
H
NH
NH
C
H
N
O
O
N
H
NH
NH
Figure 1.
the trans and cis structures of catalyst 4b (C and D) are
flexible due to the presence of –CH2– spacer between nitro-
gen and phenyl ring and hence provide unhindered access
of the reactants to the catalytic site. Similar difference in
the reaction rate is also observed in catalysts 4d and 4e
having naphthyl groups (Table 1, entries 4 and 5). Organo-
catalyst 4c derived from L-proline and ( )-1-phenyl-
ethylamine (entry 3) leads to a considerable increase in
the enantioselectivity and affords (R)-3a in 92% yield and
33% ee. Organocatalyst 4d with a naphthyl group afforded
(S)-3a with 3% ee (entry 4). Where as organocatalyst
(2S,10R/S)-4e afforded (R)-3a in 24% ee. Out of these
organocatalysts, only 4c, which is a diastereomeric mixture
of (2S,10R) and (2S,10S) diastereomers gave higher enantio-
selectivities (entry 3). To study the enantioselective cata-
lytic effect of diastereomeric catalysts 4c, the pure
diastereomers 4g and 4f were synthesized. The aldol reac-
tion with (2S,10R)-4g and (2S,10S)-4f gave (R)-3a with ee
of 45% (26 h) and 39% (6 h), respectively (entries 6 and
7). Diastereomer (2S,10S)-4f catalyzes the reaction faster
than diastereomer (2S,10R)-4g. Catalyst (2S,10R)-4h with
an ethyl group in place of the methyl, as in (2S,10R)-4g,
gave (R)-3a in 83% yield in 8 h with 46% ee (entry 8).
The catalysis of the enantioselective aldol reaction by
(2S,10R)-4h is faster than that catalyzed by (2S,10R)-4g
while the enantioselectivity is comparable. This indicates
that the diastereomeric catalysts 4g and 4h with mis-
matched configurations at the two stereogenic centres are
better than catalyst 4f with a matched configuration. Addi-
tionally catalysts 4i, 4j and 4k prepared from L-proline and
Catalyst 4a may be considered to have two structures A
and B (Fig. 1) having cis amide and the other having trans
amide linkage, respectively. In the cis structure A, the phen-
yl ring covers the catalytic nitrogen of the pyrrolidine ring
thus inhibiting the reaction, whereas in trans structure B
the catalytic nitrogen of pyrrolidine is not hindered. Both
(S)
R
N
CHO
H
O
4
O
OH
HBr
O
+
H2O
NO2
CH3
NO2
R-3a
1a
2
HN
HN
HN
CH3
HN
CH3
NH
NH
(S)
R=
4a
4b
CH3
4c
4d
4e
4f
NH
HN
(R)
HN
C2H5
NH
NH
(R)
N
N
N
4g
4h
4i
4j
4k
Scheme 1.

2110
S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2-, 3- and 4-aminopyridine,11 respectively, were screened to
determine the effect of a heteroaromatic ring. The aldol
reactions with these catalysts were run for 10 days. Catalyst
4j gave the aldol product in 52% yield and 31% ee, while 4i
was not an effective catalyst and 4k gave traces of aldol
product (R)-3a.
Table 2. Direct asymmetric aldol reaction of acetone 2 and 4-nitrobenz-
aldehyde (1a) in water catalyzed by organocatalysts 4
Entry Catalyst Time
Conversiona (%) Yieldb (%) ee (R)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4l
4 h
100
100
95
97
100
92
—
37
100
90.4
92.7
93
87
89
92
89
90
36
92
84
90
89
78
87
29
30
35
36
39
2
10
22
24
31
35
39
13
9
4m
4n
4o
4p
4q
4r
30 min
90 min
150 min
4 h
10 h
10 h
10 days
5 h
5 h
12 h
5 h
18 h
8 h
Thus, from the above results of screening it can be con-
cluded that catalysts 4g and 4h are potential organocata-
lysts for the direct asymmetric aldol reaction in water
with high activity and moderate enantioselectivity whereas
other organocatalysts derived from L-proline and aromatic
amines have been found to be less efficient catalysts.
4s
4t
4u
4v
4w
4x
4y
100
98
87
Hydrophobic effects have been invoked to explain the unu-
sual reactivity of organic reactions in water. The impor-
tance of hydrophobicity in the direct aldol reaction
catalyzed by organocatalysts in water has been further elu-
cidated by studying the reactivity and selectivity of the
organocatalysts prepared from L-proline and alkyl amines
(Scheme 2). The screening of the catalysts having butyl,
hexyl, heptyl and octyl groups revealed that enantioselec-
tivity increases with an increase in the chain length. Cata-
lyst 4o having a linear octyl chain affords an ee of 36%
(Table 2, entry 4) whereas the catalyst (2S,10R/S)-4p hav-
ing a branched heptyl chain affords (R)-3a with an ee of
39% (entry 5). The catalysts with smaller chain lengths
afforded (R)-3a with lower enantiomeric excess, thus
indicating the importance of hydrophobic effects in the
enantioselective catalysis. The hydrophobic nature of
the catalysts can be further enhanced by dialkyl groups.
Catalysts 4q–w synthesized by using dimethylamine,
diethylamine, dipropylamine, dibutylamine, dihexylamine,
dioctylamine and diisopropylamine, respectively, catalyzed
the aldol reaction of acetone 2 and 4-nitrobenzaldehyde 1a
to afford (R)-3a with ees ranging from 2% to 39%. Clearly,
the same trend follows and there is slight enhancement in
enantioselectivity due to the introduction of two alkyl
chains in the catalysts. The comparison of catalyst 4l and
catalyst 4u having an N-butyl group and an N,N-dibutyl
93
a Conversion based on 1H NMR.
b Isolated yields after column chromatography.
group, respectively, shows an increase in enantioselectivity
from 29% to 31%.
A similar comparison of catalyst 4o (R = NHC8H17) and
catalyst 4w (R = N(C8H17)2) also showed an enhancement
in enantioselectivity from ee 36% (Table 2, entry 4) to ee
39% (Table 2, entry 12). The comparison of an N,N-diiso-
propyl group (catalyst 4t) and an N,N-dipropyl group (cat-
alyst 4s) shows that the catalyst with a branched alkyl
chain 4t afforded (R)-3a with higher ee of 24% ee whereas
catalyst 4s affords (R)-3a with an ee of 22% (Table 2,
entries 8 and 9). Further, catalysts 4x and 4y having pyrrol-
idine and piperidine groups were found to be inferior
affording ees of 13% and 9%, respectively (Table 2, entries
13 and 14).
Thus the study reveals that the presence of linear hydro-
phobic groups on L-prolinamide based catalysts enhances
the enantiomeric excess in the direct aldol reaction in
water. The reaction catalyzed by the catalysts having a
monoalkyl chain (Fig. 2A) occurs at a faster rate than
the reaction catalyzed by catalysts having dialkyl chains
(Fig. 2B). This difference in reactivity indicates the involve-
ment of amide NH in the transition state of aldol reaction.
(S)
R
N
CHO
H
O
4
As is clear from Tables 1 and 2 in all the cases, the (R)-iso-
mer is predominant in the aldol product irrespective of the
catalyst used (except catalyst 4d, Table 1, entry 4). Similar
results were obtained, when employing 4f, 4g or 4h as the
organocatalysts irrespective of the stereocentre present at
the a-carbon of the amine (Table 1, entries 6, 7 and 8). It
should be noted that a similar stereochemical outcome
[(R)-isomer] can be found in proline’s enamine catalysis
in organic media.12 It may be concluded that the stereocen-
tre at the pyrrolidine ring is directing the stereochemistry of
the process. Hence, we envisioned a transition state favour-
ing re-facial attacks similar to enamine catalysis of proline
for the aldol reaction. The enantioselectivity and reactivity
of the direct aldol reaction of acetone 2 and 4-nitrobenzal-
dehyde 1a catalyzed by L-prolinamide hydrobromide cata-
lysts can be accounted for by invoking the transition state
as shown in Figure 2, involving a proton mediated six-
O
OH
HBr
O
l%
mo
20
+
H2O
NO2
NO2
2
R-3a
1a
-NHC8H17
-NHC7H15
R= -NHC4H9
-NHC6H13
4l
CH3
4m
4n
4o
-N(C3H7)2
-N(CH3)2
-N(C2H5)2
NHHC C6H13
4s
4q
4r
4p
-N(C8H17 2
)
-N(CH(CH3)CH3)2 -N(C4H9)2
-N(C6H13 2
)
4u
4v
4t
4w
N
4x
N
4y
Scheme 2.

S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2111
A
B
O
O
N
N
(S)
(S)
H
N
O
N
O
H
H
Br
Br
CH3
H
CH3
H
Figure 2.
membered cyclic transition state with additional activation
and orientation of the aldehyde by the amide proton.
The favourable hydrophobic interaction of the aryl/alkyl
groups of the catalyst and the aldehydes enforces an
asymmetric environment. In the absence of activation of
aldehyde by amide NH, the reaction is slower but enantio-
selectivity is not affected. Thus, the enantioselectivity of the
process is mainly controlled by the hydrophobic inter-
actions between the hydrophobic groups of aldehyde and
the catalysts. An increase in the hydrophobicity of the
catalyst results in an increase in the enantioselectivity of
the aldol process.
60 h (Table 3, entry 5). The lower concentration of water
leads to longer reaction time in the case of catalyst
(2S,10S)-4f and (2S,10R)-4h (Table 3, entries 9 and 12),
but the effect was not observed in the case of (2S,10R)-4g
(Table 3, entries 1–3). The aldol reaction catalyzed by
(2S,10R)-4g performed using a lesser volume of both ace-
tone (1.5 mL) and water (1.5 mL) results in a decrease in
the yield and enantioselectivity (39%) of (R)-3a (entry 6).
Additives are known to alter the reactivity and selectivity
of organic reactions, so it was planned to study the effect
of co-solvents on the aldol reaction using catalyst
(2S,10R)-4g and (2S,10S)-4h. The results are presented in
Table 4. The results show that in the case of catalyst
(2S,10R)-4g, the addition of THF improves the enantio-
selectivity in comparison to the reactions performed with-
out a co-solvent and when DMSO or DMF are used as a
co-solvent (Table 4, entries 2–4). In the case of catalyst
(2S,10S)-4f, DMF as co-solvent affords higher enantioselec-
tivity of (R)-3a (Table 4, entry 5) as compared to DMSO or
THF (entries 6 and 7). The enantioselectivity is similar to
that obtained with catalyst (2S,10R)-4g in the absence of
any co-solvent (entry 1). Thus the co-solvent does not seem
to offer any distinct advantage.
The importance of hydrophobic interactions in determin-
ing the enantioselectivity of the aldol reaction has been
known for class I aldolase enzymes13 and aldolase catalytic
antibodies14 that use enamine mechanisms for catalyzing
enantioselective aldol reaction in water. During the writing
of this work, similar observations were reported by Takabe
et al.15 using a diamine catalyst bearing hydrophobic alkyl
chains in the presence of an acid additive.
The role of water was examined in the organocatalyzed di-
rect aldol reaction (Scheme 3). The direct aldol reaction of
acetone 2 and 4-nitrobenzaldehyde 1a in dry acetone using
catalyst (2S,10R)-4g and (2S,10S)-4f gave aldol products in
traces even after 5 days (Table 3, entries 7 and 10). But
same reaction in water affords (R)-3a in 45% ee and 89%
yield. The use of water in smaller amounts led to an in-
crease in enantioselectivity to 50% (Table 3, entries 2 and
3) using catalyst (2S,10R)-4g. The same reaction when per-
formed at lower temperature 0–4 ꢁC using (2S,10R)-4g as
catalyst afforded (R)-3a in 56% ee in a reaction time of
The role of Bronsted acids in enhancing the catalytic ability
of pyrrolidine-based organocatalysts has been reported.16
Since in the present investigations, L-prolinamide hydro-
bromide derivatives have been found to be excellent cata-
lysts, it was planned to investigate the role of a counter ion
in the direct asymmetric aldol reaction in water. For this
purpose organocatalysts 4g, 6 and 7 were prepared. The
direct asymmetric aldol reaction of acetone 2 and 4-nitro-
benzaldehyde 1a catalyzed by these catalysts has been stud-
ied (Scheme 4) and the results are presented in Table 5. The
catalyst having counterion Brꢀ, Clꢀ and CF3COOꢀ gave
comparable enantiomeric excess for (R)-3a, but the effect
on the rate of reaction is tremendous. Catalyst 6 gave a fast
reaction with 100% conversion in 30 h, but the aldol reaction
catalyzed by catalysts 7 gave 63% conversion in 50 h. The
fastest but the least selective was the amine catalyst 5, which
affords (R)-3a in 3 h with 16% ee and 87% conversion.
R
CHO
O
OH
N
H
HBr
O
O
4
+
NO2
H2O
NO2
1a
R-3a
2
NH
H
C2H5
NH
H
CH3
NH
The lower enantioselectivity for the amine catalyst can be
ascribed to the competing general base catalysis. The high-
er enantioselectivity as shown by catalysts 4g, 6 and 7 can
be ascribed to the lower basic strength of the catalysts,
which inhibits the competing general base catalyzed reac-
R =
H
CH3
4f
4h
4g
Scheme 3.

2112
S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
Table 3. Effect of amount of water on the direct asymmetric aldol reaction
Entry
Catalyst (mol %)
Acetone (mL)
Water (mL)
Solvent
Acetone/water
Time
Yield (%)
3a
ee (%) (R)
1
2
3
4
5
6
7
8
9
10
11
12
13
4g (20)
4g (20)
4g (20)
4g (5)
4g (20)
4g (20)
4g (20)
4f (20)
4f (20)
4f (20)
4h (20)
4h (20)
Proline (20)
3
3
3
3
3
1.5
3
3
3
3
3
3
3
3
1:1
2:1
4:1
4:1
4:1
1:1
0
1:1
4:1
0
40 h
40 h
40 h
72 h
60 h
40 h
5 days
6 h
24 h
5 days
8 h
19 h
3 h
89
89
86
88
60
69
Traces
87
78
45
48
50
49
56a
39
nd
39
38
nd
46
49
3
1.5
0.735
0.735
0.735
1.5
0
3
0.735
0
3
0.735
3
Traces
83
83
1:1
4:1
1:1
78
a Reaction performed at 0–4 ꢁC.
Table 4. Effect of co-solvent on the aldol reaction between acetone 2 and 4-nitrobenzaldehyde 1a catalyzed by 4g and 4f
Entry
Catalyst
Acetone (mL)
Water (mL)
Solvent (1.5 mL)
Time (h)
Yielda (%)
3a
ee (R)
1
2
3
4
5
6
7
8
4g
4g
4g
4g
4f
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
—
40
24
48
24
7
20
16
10
69
80
78
69
71
85
85
60
39
40
48
39
40
26
27
32
DMSO
THF
DMF
DMF
DMSO
THF
PEG
4f
4f
4f
a Isolated yields after column chromatography.
CHO
O
OH
O
Catalyst, 20 mol%
+
H2O
NO2
H
NO2
1a
3a
2
H
H
H
N
CH3
H
CH3
H
CH3
H
CH3
H
N
N
N
N
N
H
HBr
N
H
HCl
N
H
H
O
O
O
O
TFA
5
6
7
4g
Scheme 4.
Table 5. The effect of a counter ion on organocatalyzed direct asymmetric
aldol reaction of acetone 2 with 4-nitrobenzaldehyde 1a in water
The X-ray crystal structure determination of 4g and 7 indi-
cates that the CF3COOꢀ anion is closely held by pyrrolid-
inium cation as compared to the Brꢀ ion (Figs. 3 and 4).
Since, the hydrogen bonds in case of 4g between the two
N–H hydrogens and Brꢀ ion are shown to be at a distance
Entry
Catalyst
Counter ion
Time
(h)
Conversion
(1H NMR)
ee
(%) (R)
1
2
3
4
5
—
3
40
30
50
87
95
100
63
16
45
43
45
˚
Brꢀ
of 2.62 and 2.43 A, the two N–H hydrogens bond with dif-
4g
6
Clꢀ
CF3COOꢀ
ferent bromide ions. The hydrogen bond in case of 7 be-
tween the N–H hydrogen of pyrrolidinium cation and the
carboxylate oxygen of trifluoroacetate shows a distance
7
˚
of 2.101 and 1.88 A and the two N–H hydrogens bond to
tion and favours the enantioselective nucleophilic catalysis
as observed by Spencer et al.8
different trifluoroacetate anions. Thus, the experimental re-
sults and the X-ray structure determination suggest that the

S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2113
Table 6. Direct aldol reaction of acetone 2 with different aromatic
aldehydes 1 in water, catalyzed by 4g and 4ha
Entry Aldehyde Catalyst Rxn time Conversion Yieldc ee
(1H NMR)
(R)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1a
1c
1c
1c
1c
1b
1b
1b
1b
1k
1k
1d
1d
1e
1e
1j
4g
4h
4g
4g
4h
4h
4g
4g
4h
4h
4g
4h
4g
4h
4g
4h
4g
4h
4g
4h
4g
4h
40
8
24
95
92
87
29
94
70
100
67
100
100
No reaction
No reaction
31
33
22
84
34
89
83
82
25
90
68
90
63
93
93
—
—
28
30
19
80
30
—
93
92
—
23
45
46
24
47
41
47
48
55
60
62
—
—
25
36
22
41
37
36
21
36
nd
37
118b
10
72b
18
118b
10
30
72
72
96
72
96
72
20
72
24
18
72
Figure 3. X-ray structure of 4g.
1j
17
1i
100
100
Traces
26
1i
1l
1h
24
a Aldehyde (1, 2 mmol), acetone (2, 40 mmol), 3 mL water and 20 mol %
of the catalyst stirrer at 27 1 ꢁC.
b Ratio of acetone to water is 4:1 (0.735 mL of water).
c Isolated yield after column chromatography.
was performed using catalysts 4g and 4h (Scheme 5). The
results of this investigation are presented in Table 6. In gen-
eral, it was observed that catalyst (2S,10R)-4h, catalyzes the
direct aldol reaction at a faster rate and affords aldol addi-
tion product 3 in higher enantioselectivity than catalyst
(2S,10R)-4g. The position and nature of the substituents
of the aromatic ring affects the reactivity and selectivity
of the aldol reaction.7
Figure 4. X-ray structure of 7 with benzene trapped in interstitial site.
anion has a detrimental effect on the catalytic activity, but
has no effect on the enantioselectivity of the catalyst.
Aldehydes with electron withdrawing substituents show
high reactivity. The aldol reaction of ortho-substituted
aldehydes shows higher selectivity than the aldol reaction
of para-substituted aldehydes (Table 6, entries 1, 2 and 9,
In order to explore the general scope of this methodology,
the aldol reaction of acetone and other aromatic aldehydes
H
R
(S)
N
N
4g; R= CH3
4h; R= C2H5
(R)
H
O
HBr
CHO
O
OH
R2
R3
l%
R4
R1
O
mo
20
+
Water
R4
R2
R1
R3
2
1
3
a: R1 = NO2 ; R2 = R3 = R4 = H
c: R1 = R2 = H ; R3 = NO2 ; R4 = H
e: R1 = H ; R2 = Cl ; R3 = R4 = H
i: R1 = CN ; R2 = R3 = R4 = H
k: R1 = OCH3 ; R2 = R3 = R4 = H
b: R1 = H ; R2 = NO2 ; R3 = R4 = H
d: R1 = Cl ; R2 = R3 = R4 = H
h: R1 = F ; R2 = R3 = R4 = H
j: R1 = R2 = R3 = R4 = H
l: R1 = H ; R2 R3 = C4H4; R4 = H
Scheme 5.

2114
S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
10), thus indicating that reaction occurs through a steri-
cally hindered transition state. 1-Naphthaldehyde 1l
affords the aldol product in traces (Table 6, entry 21)
whereas benzaldehyde 1h gave aldol (R)-3 in low yield
and low enantiomeric excess (Table 6, entries 17 and 18).
Thus the catalysts (2S,10R)-4g and (2S,10R)-4h catalyze
the direct asymmetric aldol reaction of acetone and substi-
tuted aromatic aldehydes, although the nature of the sub-
stituents of the aromatic aldehyde controls the overall
success of the reaction.
using 1–5% methanol in chloroform as eluent. Organic sub-
strates, aryl and alkyl amines were obtained from Aldrich
and L-proline and Boc-L-proline were procured from
Spectrochem, India and used as received. Dicyclohexylcar-
bodiimide and benzylchloroformate (CbzCl) as 50% solu-
tion in toluene were also procured from Spectrochem,
India and used directly.
4.2. Synthesis of (S)-2-(alkyl/arylcarbamoyl)pyrrolidinium
bromide 4
To an ice cold stirred solution of (S)-N-(benzyloxy-
carbonyl)proline18a (1 g, 3.4 mmol), alkyl/aryl amine (3.4
mmol) in dichloromethane (15 mL), a solution of dicyclo-
hexylcarbodiimide (0.88 g, 3.8 mmol) in dichloromethane
was added dropwise. The resulting mixture was stirred and
the temperature of the reaction mixture was allowed to
rise to room temperature. The progress of the reaction was
monitored by TLC (Rf 0.4, ethyl acetate/hexane, 2:3). After
completion of the reaction, the reaction mixture was fil-
tered and evaporated to obtain the crude product, which
on column chromatography gave (S)-2-(alkyl/arylcarba-
moyl)-N-(benzyloxycarbonyl)prolinamide as a white solid
in 65–90% yield. A mixture of (S)-2-(alkyl/arylcarb-
amoyl)-N-(benzyloxycarbonyl)prolinamide (1 g) and 33%
solution of HBr in acetic acid (3 mL) was then stirred for
3 h.18b The reaction was stopped by distillation of acetic
acid under reduced pressure and the crude product was ob-
tained as thick liquid, which on column chromatography
(60–120 mesh silica) using ethyl acetate followed by
mixture of chloroform with increasing concentration of
methanol (1–5%) as eluent gave the (S)-2-(alkyl/arylcarb-
amoyl)pyrrolidinium bromide as a pure product.
3. Conclusion
In conclusion, we have demonstrated a unique direct asym-
metric aldol reaction in water catalyzed by a small organic
molecule having a simple amide linkage for procuring chi-
ral b-hydroxyketones in good yields and good to moderate
enantioselectivities without any major side product. The
study reveals an interesting area of aqueous asymmetric
organocatalysis. The designed catalysts are multifunctional
in nature and exploit the combined effect of hydrogen
bonding and hydrophobic interactions for the enantioselec-
tive catalysis in water. Moreover, this simple amide based
organocatalysis in water provides an insight into the pep-
tide and enzyme catalysis under physiological conditions,
which may further help in the rational design of the simple
yet highly evolved organocatalysts and enzyme mimics.
Our studies indicate that small organic molecules as cata-
lysts have the ability to achieve the level of stereoselectivity
that is shown by peptide catalysts under ambient condi-
tions.17 A broad mechanistic view is being generated and
the scope of these organocatalysts for other carbon–carbon
bond formation reactions is being pursued.
4.2.1. (S)-2-(Phenylcarbamoyl)pyrrolidinium bromide 4a.
Yield, 64%; white solid, mp: 170–172 ꢁC; Rf 0.3 (metha-
nol/chloroform, 1:99); MS (m/z) FAB: 191 (M+);
½aꢁD ¼ ꢀ18:0 (c 0.38, MeOH); H NMR (D2O): d 2.09–
2.29 (m, 3H, CH2), 2.51–2.63 (m, 1H, CH2), 3.41–3.56
(m, 2H, CH2), 4.54 (t, 1H, J = 7.6 Hz, CH), 7.27–7.33
(m, 1H, ArH), 7.43–7.50 (m, 4H, ArH); 13C DEPT NMR
(CDCl3 + DMSO-d6): 22.9 (ꢀve), 29.2 (ꢀve), 45.1 (ꢀve),
58.9 (+ve), 118.7 (+ve), 123.2 (+ve), 127.6 (+ve), 136.9,
165.4.
4. Experimental
4.1. General
20
1
NMR spectra were obtained at 200 MHz (Bruker AC
200E) or 300 MHz (Jeol AL-300) for H and at 50 MHz
1
or 75 MHz for 13C NMR using either CDCl3 or D2O as
solvents with Me4Si in CDCl3 as internal standard. Chem-
ical shifts are reported in d values relative to TMS and cou-
pling constants (J) are expressed in hertz. Spectral patterns
are designated as s = singlet; d = doublet; dd = doublet of
doublets; q = quartet; t = triplet; br = broad; m = multi-
plet. When necessary, assignments were aided by DEPT-
135 and decoupling experiments. IR spectra were obtained
with Nicolet Avatar 320 FTIR and are reported in wave-
numbers (cmꢀ1). Mass spectra were recorded on GCMS-
QP-2000 mass spectrometer or Jeol SX-102 (FAB) spectro-
photometer. Analytical thin-layer chromatography (TLC)
was performed on either (i) aluminum sheets pre-coated
with silica gel 60F254 (Merck, India) or (ii) glass plates
(7.5 · 2.5 cm) coated with silica gel GF-254 (Spectrochem
India) containing 13% calcium sulfate as binder and vari-
ous combinations of ethyl acetate and hexane were used
as eluents. Visualization of the spots was accomplished
by exposure to UV light or iodine vapours. Column chro-
matography was performed on silica gel (100–200 mesh)
4.2.2. (S)-2-(Benzylcarbamoyl)pyrrolidinium bromide 4b.
Yield, 79%; brown liquid; Rf 0.3 (methanol/chloroform,
20
1:99); MS (m/z) FAB: 205 (M+); ½aꢁD ¼ ꢀ29:0 (c 0.61,
MeOH); IR (neat): 1230, 1520, 1690, 2410, 2920,
1
3060 cmꢀ1; H NMR (CDCl3): d 1.87–1.99 (m, 3H, CH2),
2.48–2.53 (m, 1H, CH2), 3.27–3.40 (m, 2H, CH2), 4.34
(dd, 1H, J = 15.3 and 5.7 Hz, CH2), 4.44 (dd, 1H,
J = 15.3 and 6.0 Hz, CH2), 4.78–4.82 (m, 1H, CH2),
7.20–7.29 (m, 5H, ArH), 8.64 (t, 1H, J = 6.0 Hz, NH);
13C DEPT NMR (CDCl3 + DMSO-d6): d 23.7 (ꢀve),
29.9 (ꢀve), 42.9 (ꢀve), 46.0 (ꢀve), 59.2 (+ve), 126.8
(+ve), 127.1 (+ve), 128.0 (+ve), 137.4, 167.8.
4.2.3. (2S,10R/S)-2-(10-Phenylethylcarbamoyl)pyrrolidinium
bromide 4c. Yield, 57%; pale yellow liquid as a mixture of
two diastereomers (2S,10R) and (2S,10S); Rf 0.2 (methanol/
20
chloroform, 1:99); MS (m/z) FAB: 219 (M+); ½aꢁD ¼ ꢀ28:5

S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2115
20
(c 0.56, MeOH); IR (neat): 1680, 2400, 2750, 3020 cmꢀ1
;
(m/z) FAB: 219 (M+); ½aꢁD ¼ þ39:0 (c 0.34, MeOH); IR
1H NMR (CDCl3): d 1.51 (d, 3H, J = 6.9 Hz, CH3),
1.81–2.03 (m, 4H, CH2 and NH), 2.53–2.58 (m, 1H,
CH2), 3.16–3.47 (m, 4H, CH2), 4.76–4.84 (m, 1H, CH),
4.89–5.01 (m, 1H, CH), 7.19–7.41 (m, 5H, ArH), 8.71 (t,
1H, J = 3.4 Hz, NH); 13C DEPT NMR (CDCl3): d 22.4
(+ve), 23.9 (+ve), 30.3 (+ve), 30.6 (+ve), 46.6 (ꢀve), 46.7
(ꢀve), 49.9 (+ve), 50.0 (+ve), 59.4 (+ve), 59.5 (+ve),
125.5 (+ve), 125.9 (+ve), 126.8 (+ve), 126.9 (+ve), 128.3
(+ve), 128.7 (+ve), 143.0, 143.3, 167.5, 167.7.
(KBr): 1672, 2979, 3071, 3274 cmꢀ1; H NMR (D2O): d
1
1.37 (d, 3H, J = 6.9 Hz, CH3), 1.86–2.05 (m, 3H, CH2),
2.34–2.41 (m, 1H, CH2), 3.24–3.35 (m, 2H, CH2), 4.22–
4.27 (m, 1H, CH), 4.84 (q, 1H, J = 6.9 Hz, CH); 1H
NMR (CDCl3): d 1.51 (d, 3H, J = 6.9 Hz, CH3), 1.90–
1.98 (m, 4H, CH2 and NH), 2.49–2.57 (m, 1H, CH2),
3.18–3.25 (m, 1H, CH2), 3.29–3.35 (m, 1H, CH2), 4.73–
4.77 (m, 1H, CH), 4.86 (t, 1H, J = 7.2 Hz, CH), 7.21–
7.38 (m, 5H, ArH), 8.63 (d, 1H, J = 7.2 Hz, NH); 13C
DEPT NMR (CDCl3): d 22.5 (+ve), 24.2 (ꢀve), 30.8
(ꢀve), 46.8 (ꢀve), 50.3 (+ve), 59.7 (+ve), 126.3 (+ve),
127.2 (+ve), 128.4 (+ve), 128.9 (+ve), 143.2, 167.8.
4.2.4. (S)-2-(Naphth-10-ylcarbamoyl)pyrrolidinium bromide
4d. Yield, 65%; white solid; mp: 213–215 ꢁC; Rf 0.2
(methanol/chloroform, 1:99); MS (m/z) FAB: 241 (M+);
20
½aꢁD ¼ ꢀ16:0 (c 0.54, MeOH); IR (KBr): 1679, 2892,
4.2.7.1. X-ray analysis of compound 4g. The diffraction
data were obtained with graphite-monochromated Mo Ka
radiation on Nonius MACH3 diffractometer at 293(2) K.
Standard reflection for each data set showed no significant
decrease in intensity through the acquisition. The structure
was solved by direct method and refined by full matrix least
square on F. The crystallographic calculations were per-
formed using Argus (Nonius, MACH3 software) for data
collection, and cell refinement, and Maxus (Nonius
software) for data reduction. SHELXS-97 software was
used for structure solution and refinement. Crystal
data: C13H19BrN2O M = 299.21, orthorhombic, P 21 21
1
3013, 3149, 3249 cmꢀ1; H NMR (CDCl3 + DMSO-d6): d
2.08–2.69 (m, 4H, CH2), 3.39–3.45 (m, 1H, CH2), 3.49–
3.55 (m, 1H, CH2), 5.01 (t, 1H, J = 7.5 Hz, CH), 7.43–
7.55 (m, 3H, NapH), 7.18 (d, 1H, J = 8.1 Hz, NapH),
7.78–7.86 (m, 2H, NapH), 8.11 (d, 1H, J = 8.1 Hz, NapH),
10.43 (br s, 1H, NH); 13C DEPT NMR (CDCl3 + DMSO-
d6): 23.6 (ꢀve), 30.2 (ꢀve), 45.8 (ꢀve), 59.5 (+ve), 121.4
(+ve), 122.0 (+ve), 124.9 (+ve), 125.7 (+ve), 127.4, 127.8
(+ve), 131.7, 133.5, 167.5.
4.2.5. (2S,10R/S)-2-(10-Naphth-100-yl-ethylcarbamoyl)-pyrrol-
idinium bromide 4e. Yield 62%; as a mixture of two dia-
stereomers, 2S,10R and 2S,10S; white solid; mp: 180–
182 ꢁC; Rf 0.2 (methanol/chloroform, 1:99); MS (m/z)
˚
˚
˚
21, a = 5.3300(7) A, b = 11.2870(9) A, c = 23.603(2) A,
3
˚
b = 90.00ꢁ, V = 1419.9(3) A , T = 293(2) K, l(Mo Ka) =
2.883 cmꢀ1, R = 0.0597, Rw = 0.1388, GOF = 1.073, 1490
unique reflections with [I > 2r(I)]. The details of the crystal
data have been deposited with Cambridge Crystallographic
Data Centre as supplementary publication No. CCDC-
616021.
20
1
FAB: 269 (M+); ½aꢁD ¼ ꢀ17:5 (c 0.89, MeOH); H NMR
(CDCl3): d 1.54–1.92 (m, 4H, CH2 and NH), 1.62 (d, 3H,
J = 6.9 Hz, CH3), 2.29–2.42 (m, 0.5H, diastereomeric H
of CH2), 2.43–2.57 (m, 0.5H, diastereomeric H of CH2),
2.90–3.23 (m, 2H, CH2), 4.78 (q, 1H, J = 8.4 Hz, CH),
5.75 (sep, 1H, J = 6.9 Hz, CH), 7.37–7.55 (m, 3H, NapH),
7.66–7.74 (m, 3H, NapH), 7.80–7.86 (m, 1H, NapH), 7.98–
8.03 (m, 1H, NapH), 8.73 (d, 1H, J = 7.5 Hz, NH of one
diastereomer), 8.89 (d, 0.5H, J = 7.8 Hz, NH of one diaste-
reomer); 13C DEPT NMR (CDCl3 + DMSO-d6): d 13.4
(+ve), 20.7 (+ve), 20.8 (+ve), 23.3 (ꢀve), 29.8 (ꢀve), 44.8
(+ve), 44.9 (+ve), 45.6 (ꢀve), 58.7 (+ve), 59.5 (ꢀve),
121.7 (+ve), 122.0 (+ve), 122.1 (+ve), 122.4 (+ve), 124.7
(+ve), 124.9 (+ve), 125.4 (+ve), 125.6 (+ve), 126.9 (+ve),
127.0 (+ve), 128.0 (+ve), 128.1 (+ve), 129.7, 129.8, 132.8,
132.9, 138.4, 166.4, 166.7.
4.2.8. (2S,10R)-2-(10-Phenylpropylcarbamoyl)pyrrolidinium
bromide 4h. Yield, 55%; low melting yellow solid; Rf 0.2
(methanol/chloroform, 1:99); MS (m/z) FAB: 233 (M+);
20
½aꢁD ¼ þ42:0 (c 0.39, MeOH); IR (neat) 1675, 2967, 3062,
3208 cmꢀ1; H NMR (CDCl3): d 0.89 (t, 3H, J = 7.2 Hz,
1
CH3), 1.75–2.00 (m, 6H, CH2 and NH), 2.54–2.58 (m, 1H,
CH2), 3.16–3.22 (m, 1H, CH2), 3.28–3.34 (m, 1H, CH2),
4.62 (q, 1H, J = 7.2 Hz, CH), 4.79–4.82 (m, 1H, CH),
7.18–7.38 (m, 5H, ArH), 8.75 (d, 1H, J = 8.1 Hz, NH);
13C DEPT NMR (CDCl3): 11.0 (+ve), 24.3 (ꢀve), 29.6
(ꢀve), 31.1 (ꢀve), 46.9 (ꢀve), 56.5 (+ve), 59.8 (+ve),
126.9 (+ve), 127.0 (+ve), 128.3 (+ve), 142.2, 168.1.
4.2.6.
(2S,10S)-2-(10-Phenylethylcarbamoyl)pyrrolidinium
bromide 4f. Yield, 65%; low melting yellow solid; Rf 0.2
4.2.9. (S)-2-(Pyridinium-20-ylcarbamoyl)pyrrolidinium di-
(methanol/chloroform, 1:99); MS (m/z) FAB: 219 (M+);
bromide 4i. Yield, 60%; brown liquid; Rf 0.2 (methanol/
20
20
1
½aꢁD ¼ ꢀ114:8 (c 0.25, MeOH); H NMR (CDCl3): d 1.54
(d, 3H, J = 6.9 Hz, CH3), 1.88–2.04 (m, 4H, CH2, and
NH), 2.62–2.68 (m, 1H, CH2), 3.25–3.33 (m, 1H, CH2),
3.43–3.49 (m, 1H, CH2), 4.88–4.92 (m, 1H, CH), 4.90–
5.02 (m, 1H, CH), 7.20–7.32 (m, 5H, ArH), 8.77 (d, 1H,
J = 5.4 Hz, NH); 13C DEPT NMR (CDCl3): d 22.6
(+ve), 24.2 (ꢀve), 30.6 (ꢀve), 46.8 (ꢀve), 50.2 (+ve), 59.6
(+ve), 125.6 (+ve), 126.9 (+ve), 127.1 (+ve), 128.4 (+ve),
128.8 (+ve), 143.4, 167.5.
chloroform, 1:99); MS (m/z) FAB: 192 (M+); ½aꢁD ¼ þ1:5
(c 0.80, MeOH); IR (neat): 1640, 1745, 3418 cmꢀ1; IR
1
(neat): H NMR (D2O): d 2.00–2.17 (m, 3H, CH2), 2.37–
2.42 (m, 1H, CH2), 3.34–3.46 (m, 2H, CH2), 4.31 (t, 2H,
J = 7.8 Hz, CH), 6.90 (t, 1H, J = 6.9 Hz, PyH), 7.02 (d,
1H, J = 8.1 Hz, PyH), 7.78 (d, 2H, J = 6.9 Hz, PyH),
7.90 (t, 1H, J = 8.1 Hz, PyH); 13C DEPT NMR (CDCl3 +
DMSO-d6): d 22.3 (ꢀve), 27.3 (ꢀve), 44.7 (ꢀve), 58.2
(+ve), 111.0 (+ve), 112.9 (+ve), 133.7 (+ve), 142.4 (+ve),
153.1, 169.4.
4.2.7. (2S,10R)-2-(10-Phenylethylcarbamoyl)pyrrolidinium
bromide 4g. Yield, 52%; white crystalline solid; mp:
108–110 ꢁC; Rf 0.2 (methanol/chloroform, 1:99); MS
4.2.10. (S)-2-(Pyridinium-30-ylcarbamoyl)pyrrolidinium di-
bromide 4j. Yield, 62%; sticky solid; Rf 0.2 (methanol/

2116
S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
20
chloroform, 1:99); MS (m/z) FAB: 192 (M+); ½aꢁD ¼ þ4:0
0.52, MeOH); IR (neat): 1675, 2927, 3222 cmꢀ1 1H
;
(c 0.70, MeOH); IR (neat): 1530, 1650, 2410, 2990,
NMR (D2O): d 0.84–0.88 (diffuse t, 3H, CH3), 1.25–1.32
(m, 10H, CH2), 1.48–1.57 (m, 2H, CH2), 2.01–2.10 (m,
3H, CH2), 2.40–2.48 (m, 1H, CH2), 3.14–3.34 (m, 2H,
CH2), 3.35–3.47 (m, 2H, CH2), 4.31–4.36 (m 1H, CH);
13C DEPT NMR (CDCl3): d 13.9 (+ve), 22.5 (ꢀve), 24.4
(ꢀve), 26.8 (ꢀve), 29.0 (ꢀve), 29.1 (ꢀve), 30.9 (ꢀve), 31.7
(ꢀve), 40.1 (ꢀve), 46.9 (ꢀve), 59.7 (+ve), 168.4.
3010 cmꢀ1; H NMR (D2O): d 2.12–2.30 (m, 3H, CH2),
1
2.57–2.62 (m, 1H, CH2), 3.46–3.57 (m, 2H, CH2), 4.66
(dd, 1H, J = 9.0 and 6.6 Hz, CH), 8.03–8.08 (dd, 1H,
J = 8.5 and 6.3 Hz, PyH), 8.51–8.55 (d, 2H, J = 8.5 Hz,
PyH), 8.57–8.60 (m, 1H, PyH), 9.27 (diffused d, 1H,
J = 2.4 Hz, PyH); 13C DEPT NMR (CDCl3 + DMSO-
d6): d 23.6 (ꢀve), 29.7 (ꢀve), 55.1 (ꢀve), 59.8 (+ve),
127.9 (+ve), 132.2 (+ve), 135.0 (+ve), 137.5 (+ve), 137.6,
168.0.
4.2.16. (S)-2-(10-Methylheptylcarbamoyl)pyrrolidinium bro-
mide 4p. Yield, 61%; yellow solid, mp: 118–120 ꢁC; Rf 0.4
(methanol/chloroform, 1:99); MS (m/z) FAB: 227 (M+);
4.2.11. (S)-2-(Pyridinium-40-ylcarbamoyl)pyrrolidinium di-
20
½aꢁD ¼ ꢀ15:5 (c 0.62, MeOH); IR (neat): 1670, 2933,
1
3216, 3412 cmꢀ1; H NMR (CDCl3): d 1.16–1.43 (m, 7H,
bromide 4k. Yield, 60%; brown liquid; Rf 0.2 (methanol/
20
chloroform, 1:99); MS (m/z) FAB: 192 (M+); ½aꢁD ¼ þ2:5
CH2 and CH3), 1.56–1.91 (m, 4H, CH2 and CH3), 2.01–
2.15 (m, 3H, CH2), 2.64–2.70 (m, 1H, CH2), 3.43–3.46
(m, 1H, CH2), 3.56–3.59 (m, 1H, CH2), 3.60–3.78 (m,
1H, CH), 4.77–4.83 (m, 1H, CH), 8.09 (d, 1H,
J = 7.8 Hz, NH); 13C DEPT NMR (CDCl3): d 24.3, 24.4,
24.7, 24.8, 25.2, 30.7, 31.1, 32.3, 32.4, 47.1, 49.6, 59.7,
167.5.
(c 0.65, MeOH); 1H NMR (D2O): d 2.00–2.30 (m, 3H,
CH2), 2.56–2.64 (m, 1H, CH2), 3.41–3.57 (m, 2H, CH2),
4.64–4.81 (m, 1H, CH), 8.08 (d, 2H, J = 7.2 Hz, PyH),
8.61 (d, 2H, J = 7.2 Hz, PyH); 13C DEPT NMR (CDCl3 +
DMSO-d6): d 23.1 (ꢀve), 29.3 (ꢀve), 45.6 (ꢀve), 59.7 (+ve),
114.4 (+ve), 135.0 (+ve), 143.5 (+ve), 150.3, 170.4.
4.2.12. (S)-2-(Butylcarbamoyl)pyrrolidinium bromide 4l.
Yield, 65%; pale yellow liquid; Rf 0.4 (methanol/chloro-
4.2.17. (S)-2-(N,N-Dimethylcarbamoyl)pyrrolidinium bro-
mide 4q. Yield, 55%; brown liquid; Rf 0.4 (methanol/chlo-
20
form, 1:99); MS (m/z) FAB: 171 (M+); ½aꢁD ¼ ꢀ14:5 (c
20
roform, 1:99); MS (m/z) FAB: 143 (M+); ½aꢁD ¼ ꢀ41:0 (c
1
0.29, MeOH); IR (neat): 1667, 2931, 3221, 3406 cmꢀ1; H
0.44, MeOH); IR (neat): 1660, 2400, 2995, 3015,
3130 cmꢀ1 1H NMR (CDCl3 + DMSO-d6): d 1.61–1.94
;
NMR (D2O): d 0.87–0.95 (diffused t, J = 7.5 Hz, 3H,
CH3), 1.26–1.43 (m, 2H, CH2), 1.59–1.81 (m, 2H, CH2),
1.98–2.09 (m, 3H, CH2), 2.39–2.50 (m, 1H, CH2), 3.16–
3.33 (m, 2H, CH2), 3.38–3.55 (m, 2H, CH2), 4.32–4.36
(m, 1H, CH); 13C DEPT NMR (CDCl3): d 13.5 (+ve),
19.6 (ꢀve), 24.6 (ꢀve), 27.5 (ꢀve), 28.5 (ꢀve), 40.3 (ꢀve),
47.1 (ꢀve), 59.7 (+ve), 168.3.
(m, 4H, CH2 and NH), 2.85–2.95 (m, 2H, CH2), 2.98 (s,
3H, CH3), 3.03 (s, 3H, CH3), 3.06–3.22 (m, 1H, CH2),
4.00 (t, 1H, J = 6.3 Hz, CH); 13C DEPT NMR (CDCl3):
d 24.7 (+ve), 29.3 (+ve), 36.1 (ꢀve), 36.8 (ꢀve), 46.5
(ꢀve), 58.0 (ꢀve), 168.5.
4.2.18. (S)-2-(N,N-Diethylcarbamoyl)pyrrolidinium bromide
4r. Yield, 55%; brown liquid; Rf 0.4 (methanol/chloro-
4.2.13. (S)-2-(Hexylcarbamoyl)pyrrolidinium bromide 4m.
Yield, 65%; brown liquid; Rf 0.4 (methanol/chloroform,
20
form, 1:99); ½aꢁD ¼ ꢀ41:6 (c 0.31, MeOH); 1H NMR
20
1:99); MS (m/z) FAB: 199 (M+); ½aꢁD ¼ ꢀ21:0 (c 0.27,
(CDCl3): d 1.15 (t, 3H, J = 7.2 Hz, CH3), 1.28 (t, 3H,
J = 7.2 Hz, CH3), 1.77 (br s, 1H, NH), 1.84–1.96 (m, 1H,
CH2), 2.02–2.13 (m, 1H, CH2), 2.20–2.92 (m, 1H, CH2),
2.53–2.60 (m, 1H, CH2), 3.30–3.53 (m, 5H, CH2), 3.58–
3.75 (m, 1H, CH2), 4.81 (br t, 1H, CH); 13C DEPT
NMR (CDCl3): d 12.6 (+ve), 14.0 (+ve), 25.0 (ꢀve), 30.1
(ꢀve), 40.7 (ꢀve), 41.7 (ꢀve), 46.7 (ꢀve), 58.3 (+ve), 167.2.
MeOH); IR (neat): 1675, 2930, 3223 cmꢀ1 1H NMR
;
(D2O): d 0.87 (diffused t, 3H, J = 6.6 Hz, CH3), 1.26–1.34
(m, 6H, CH2), 1.40–1.60 (m, 2H, CH2), 1.99–2.06 (m,
3H, CH2), 2.38–2.44 (m, 1H, CH2), 3.15–3.40 (m, 2H,
CH2), 3.33–3.43 (m, 2H, CH2), 4.24–4.29 (m, 1H, CH);
13C DEPT NMR (CDCl3): d 13.9 (+ve), 22.4 (ꢀve), 24.5
(ꢀve), 26.5 (ꢀve), 29.0 (ꢀve), 30.8 (ꢀve), 31.3 (ꢀve), 39.9
(ꢀve), 46.9 (ꢀve), 59.8 (+ve), 169.1.
4.2.19. (S)-2-(N,N-Dipropylcarbamoyl)pyrrolidinium bro-
mide 4s. Yield, 60%; pale yellow liquid; Rf 0.4 (metha-
4.2.14. (S)-2-(Heptylcarbamoyl)pyrrolidinium bromide 4n.
Yield, 65%; yellow solid, mp: 90–92 ꢁC; Rf 0.4 (methanol/
nol/chloroform, 1:99); MS (m/z) FAB: 199 (M+);
20
20
½aꢁD ¼ ꢀ40:0 (c 0.33, MeOH); IR (neat): 1625, 2400,
chloroform, 1:99); MS (m/z) FAB: 213 (M+); ½aꢁD ¼ ꢀ29:0
1
2980, 3420, 3460 cmꢀ1; H NMR (D2O): d 0.67–0.76 (m,
(c 1.43, MeOH); IR (neat): 1672, 2930, 3214 cmꢀ1 1H
;
6H, CH3), 1.39–1.52 (m, 4H, CH2), 1.76–1.94 (m, 3H,
CH2), 2.37–2.45 (m, 1H, CH2), 2.97–3.35 (m, 6H, CH2),
4.53 (t, 1H, J = 8.1 Hz, CH); 13C DEPT NMR (CDCl3):
d 11.2 (+ve), 20.5 (ꢀve), 21.8 (ꢀve), 25.1 (ꢀve), 30.2
(ꢀve), 46.7 (ꢀve), 47.8 (ꢀve), 49.0 (ꢀve), 58.2 (+ve), 167.6.
NMR (D2O): d 0.84–0.89 (diffuse t, 3H, CH3), 1.15–1.38
(m, 8H, CH2), 1.44–1.62 (m, 2H, CH2), 1.90–2.10 (m,
3H, CH2), 2.37–2.48 (m, 1H, CH2), 3.16–3.34 (m, 2H,
CH2), 3.51–3.65 (m, 2H, CH2), 4.27–4.34 (m, 1H, CH);
13C DEPT NMR (CDCl3): d 13.9 (+ve), 22.4 (ꢀve), 24.7
(ꢀve), 26.8 (ꢀve), 28.8 (ꢀve), 30.9 (ꢀve), 31.6 (ꢀve), 32.3
(ꢀve), 40.1 (ꢀve), 46.9 (ꢀve), 59.7 (+ve), 168.2.
4.2.20. (S)-2-(N,N-diisopropylcarbamoyl)pyrrolidinium bro-
mide 4t. Yield, 65%; sticky yellow solid; Rf 0.4 (methanol/
20
4.2.15. (S)-2-(Octylcarbamoyl)pyrrolidinium bromide 4o.
Yield, 59%; pale yellow liquid; Rf 0.3 (methanol/chloro-
chloroform, 1:99); MS (m/z) FAB: 198 (M+); ½aꢁD ¼ ꢀ18:0
(c 1.19, MeOH); IR (neat): 1671, 2933, 3215 cmꢀ1 1H
;
20
form, 1:99); MS (m/z) FAB: 227 (M+); ½aꢁD ¼ ꢀ19:0 (c
NMR (CDCl3): d 1.12–1.39 (m, 6H, CH3), 1.56–1.98 (m,

S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2117
7H, CH3 and NH), 1.98–2.22 (m, 3H, CH2), 2.64–2.72 (m,
1H, CH2), 3.20–3.35 (m, 1H, CH), 3.40–3.48 (m, 1H, CH2),
3.50–3.61 (m, 1H, CH2), 3.62–3.78 (m, 1H, CH), 4.81–4.88
(m, 1H, CH); 13C DEPT NMR (CDCl3): d 24.2 (+ve), 24.5
(+ve), 24.7 (+ve), 25.1 (+ve), 30.6 (+ve), 31.0 (+ve), 32.3
(+ve), 47.1 (ꢀve), 49.5 (ꢀve), 59.6 (ꢀve), 167.4.
1H, J = 6.6 Hz, CH); 13C DEPT NMR (CDCl3): d 21.0
(ꢀve), 22.9 (ꢀve), 23.3 (ꢀve), 24.2 (ꢀve), 24.9 (ꢀve), 28.5
(ꢀve), 42.7 (ꢀve), 45.5 (ꢀve), 45.7 (ꢀve), 57.4 (+ve), 165.3.
4.3. Synthesis of (2S,10R)-2-(10-Phenylethylcarbamoyl)-
pyrrolidinium chloride 6
4.2.21. (S)-2-(N,N-Dibutylcarbamoyl)pyrrolidinium bromide
4u. Yield,60%;paleyellowliquid;Rf 0.4(methanol/chloro-
To a mixture of 4g (1 g, 3.3 mmol) in ether (15 mL), triethyl
amine (0.37 g, 3.6 mmol) was added and stirred for 3 h.
The reaction mixture was filtered and evaporated to obtain
the crude product. Column chromatography (60–120 mesh
silica) of the crude product using ethyl acetate yielded an
acid free amide as a yellow thick liquid (78% yield). The
ether solution of acid free amide was stirred with concen-
trated HCl (5.0 mmol of 37% HCl) for 3 h. The evapora-
tion of the solvent under reduced pressure gave the crude
product, which on column chromatography (60–120 mesh
silica) using increasing concentration of methanol in
dichloromethane (1–5%) as eluent gave (2S,10R)-2-(10-phen-
ylethylcarbamoyl)pyrrolidinium chloride as pure product
(0.56 g).
20
form, 1:99); MS (m/z) FAB: 227 (M+); ½aꢁD ¼ ꢀ38:0 (c
0.33, MeOH); IR (neat): 1650, 2926, 3403 cmꢀ1 1H
;
NMR (D2O): d 0.70–0.77 (m, 6H, CH3), 1.10–1.19 (m,
4H, CH2), 1.31–1.47 (m, 4H, CH2), 1.77–1.93 (m, 3H,
CH2), 2.30–2.42 (m, 1H, CH2), 3.05–334 (m, 6H, CH2),
4.84 (t, 1H, J = 8.4 Hz, CH); 13C DEPT NMR (CDCl3):
d 12.6 (+ve), 18.5 (ꢀve), 18.6 (ꢀve), 18.7 (ꢀve), 23.3
(ꢀve), 28.0 (ꢀve), 28.7 (ꢀve), 29.3 (ꢀve), 44.5 (ꢀve), 45.6
(ꢀve), 46.0 (ꢀve), 57.0 (+ve), 166.7.
4.2.22. (S)-2-(N,N-Dihexylcarbamoyl)pyrrolidinium bro-
mide 4v. Yield, 58%; yellow sticky solid; Rf 0.4 (metha-
nol/chloroform, 1:99); MS (m/z) FAB: 283 (M+);
20
½aꢁD ¼ ꢀ17:5 (c 0.68, MeOH); IR (neat): 1671, 2857,
1
4.3.1. (2S,10R)-2-(10-Phenylethylcarbamoyl)pyrrolidinium
chloride 6d. Yield, 65%; yellow thick liquid; Rf 0.3 (meth-
2934, 3214 cmꢀ1; H NMR (D2O): d 0.98–1.21 (m, 11H,
CH3 and CH2), 1.38–1.72 (m, 10H, CH2), 1.82–1.92 (m,
6H, CH2), 2.20–2.29 (m, 1H, CH2), 2.90–3.50 (m, 4H,
CH2), 4.09–4.14 (m, 1H, CH); 13C DEPT NMR (CDCl3):
d 24.2 (ꢀve), 24.3 (ꢀve), 24.4 (ꢀve), 24.6 (ꢀve), 24.7
(ꢀve), 25.1 (ꢀve), 30.6 (ꢀve), 31.0 (ꢀve), 32.1 (ꢀve), 32.2
(ꢀve), 47.2 (ꢀve), 49.4 (+ve), 51.0 (+ve), 59.6 (+ve), 167.5.
anol/chloroform, 1:99); MS (m/z) FAB: 219 (M+);
20
½aꢁD ¼ ꢀ37:0 (c 0.32, MeOH); 1H NMR (D2O): d 1.49
(d, 3H, J = 7.2 Hz, CH3), 2.04–2.17 (m, 3H, CH2), 2.45–
2.2.53 (m, 1H, CH2), 3.36–3.47 (m, 2H, CH2), 4.45 (t,
1H, J = 7.5 Hz, CH), 4.92 (q, 1H, J = 6.6 Hz, CH), 7.18–
7.30 (m, 5H, ArH), 8.52 (d, 1H, J = 7.5 Hz, NH); 13C
DEPT NMR (CDCl3): d 22.5 (+ve), 24.2 (ꢀve), 30.7
(ꢀve), 46.1 (ꢀve), 50.1 (+ve), 59.7 (+ve), 126.3 (+ve),
127.0 (+ve), 128.5 (+ve), 143.3, 167.9.
4.2.23. (S)-2-(N,N-Dioctylcarbamoyl)pyrrolidinium bromide
4w. Yield, 68%; yellow solid, mp: 110–114 ꢁC; Rf 0.4
(methanol/chloroform, 1:99); MS (m/z) FAB: 339 (M+);
20
½aꢁD ¼ ꢀ26:0 (c 0.49, MeOH); IR (neat): 1670, 2932,
1
3214 cmꢀ1; H NMR (D2O): d 0.84–1.25 (m, 15H, CH3
4.4. Synthesis of (2S,10R)-2-(10-phenylethylcarbamoyl)-
pyrrolidinium trifluoroacetate 7
and CH2), 1.36–1.73 (m, 12H, CH2), 1.76–1.94 (m, 7H,
CH2), 2.19–2.28 (m, 1H, CH2), 2.90–3.10 (m, 1H, CH2),
3.18–3.31 (m, 2H, CH2), 3.40–3.50 (m, 1H, CH2), 4.09–
4.14 (m, 1H, CH); 13C DEPT NMR (CDCl3): d 23.6
(ꢀve), 23.8 (ꢀve), 24.3 (ꢀve), 24.8 (ꢀve), 30.1 (ꢀve), 30.2
(ꢀve), 31.9 (ꢀve), 38.9 (ꢀve), 39.2 (ꢀve), 39.5 (ꢀve), 39.7
(ꢀve), 40.0 (ꢀve), 45.8 (ꢀve), 48.4 (+ve), 49.9 (+ve), 58.9
(+ve), 166.6.
To an ice cold stirred solution of Boc-proline (1 g,
4.6 mmol), and (R)-1-phenylethylamine (4.6 mmol) in
dichloromethane (15 mL), a solution of dicyclohexylcarbo-
diimide (4.6 mmol) in dichloromethane was added drop-
wise followed by the addition of a catalytic amount of
DMAP. The resulting mixture was stirred and the temper-
ature of the reaction mixture was allowed to rise to room
temperature. The progress of the reaction was monitored
by TLC (Rf 0.4, ethyl acetate/hexane, 2:3). After comple-
tion of the reaction, the reaction mixture was filtered and
evaporated to obtain crude product, which on column
chromatography gave (2S,10R)-2-(10-phenylethylcarba-
moyl)-N-(tert-butyl ester)prolinamide (1.3 g). To a mix-
ture of (2S,10R)-2-(10-phenylethylcarbamoyl)-N-(tert-butyl
ester)prolinamide (1.3 g, 4.03 mmol) and dichloromethane
(15 mL), trifluoroacetic acid (0.48 g, 4.03 mmol) was added
and stirred for 6 h. The reaction was stopped the solvent re-
moved under reduced pressure to obtain the crude product
as a thick liquid. The column chromatography (60–120
mesh silica) of the crude using ethyl acetate followed by a
mixture of chloroform with increasing concentration of
methanol (1–5%) as eluent gave the (2S,10R)-2-(10-phenyl-
ethylcarbamoyl)pyrrolidinium trifluoroacetate as pure
product (0.71 g).
4.2.24. (S)-2-(Pyrrolidine-10-carbonyl)pyrrolidinium bromide
4x. Yield, 50%; brown liquid; Rf 0.4 (methanol/chloro-
20
form, 1:99); MS (m/z) FAB: 169 (M+); ½aꢁD ¼ ꢀ55:5 (c
0.80, MeOH); IR (neat): 1649, 2940, 3406 cmꢀ1 1H
;
NMR d (D2O) 1.88–2.12 (m, 7H, CH2), 2.51–2.58 (m,
1H, CH2), 3.35–3.60 (m, 6H, CH2), 4.57 (t, 1H,
J = 6.9 Hz, CH); 13C DEPT NMR (CDCl3): d 23.6
(ꢀve), 24.1 (ꢀve), 25.5 (ꢀve), 28.5 (ꢀve), 46.3 (ꢀve), 46.4
(ꢀve), 46.5 (ꢀve), 58.9 (+ve), 166.2.
4.2.25. (S)-2-(Piperidine-10-carbonyl)pyrrolidinium bromide
4y. Yield, 55%; brown liquid; Rf 0.4 (methanol/chloro-
20
form, 1:99); MS (m/z) FAB: 183 (M+); ½aꢁD ¼ ꢀ53:0 (c
0.54, MeOH); IR (neat): 1645, 2939, 3424 cmꢀ1 1H
;
NMR (CDCl3): d 1.56–1.76 (m, 6H), 1.87–1.93 (m, 1H,
CH2), 2.01–2.12 (m, 1H, CH2), 2.14–2.25 (m, 1H, CH2),
2.50–2.62 (m, 1H, CH2), 3.43–3.62 (m, 6H, CH2), 4.91 (t,

2118
S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
4.4.1. (2S,10R)-2-(10-Phenylethylcarbamoyl)pyrrolidinium
trifluoroacetate 7. Yield, 65%; white crystalline solid;
mp: 118–120 ꢁC; Rf 0.3 (methanol/chloroform, 1:99); MS
H, i-PrOH/hexane 30:80), UV 254 nm, flow rate 1.0 mL/
min. R-isomer, tR 7.8 min and S-isomer, tR 6.7 min.
20
1
(m/z) FAB: 219 (M+); ½aꢁD ¼ þ29:5 (c 0.15, MeOH); H
NMR (CDCl3): d 1.44 (d, 3H, J = 6.9 Hz, CH3), 1.80–
1.88 (m, 4H, CH2 and NH), 2.00–2.30 (m, 1H, CH2),
3.16–3.24 (m, 2H, CH2), 4.34–4.39 (m, 1H, CH), 4.95 (q,
1H, J = 6.6 Hz, CH), 7.35–7.50 (m, 5H, ArH); 13C DEPT
NMR (CDCl3): d 21.8 (+ve), 24.2 (ꢀve), 29.8 (ꢀve), 46.1
(ꢀve), 50.0 (+ve), 59.5 (+ve), 126.0 (+ve), 127.3 (+ve),
128.6 (+ve), 142.9, 167.5.
4.5.3. (R)-4-Hydroxy-4-(30-nitrophenyl)butan-2-one 3c.10
25
Yield, 68%; ½aꢁD ¼ þ35:0 (c 1.14, CH2Cl2); enantiomeric
excess: 47%, determined by HPLC (Diacel Chiralpak AS-
H, i-PrOH/hexane 30:70), UV 254 nm, flow rate 1.0 mL/
min. R-isomer, tR 14.1 min and S-isomer, tR 17.6 min.
4.5.4. (R)-4-Hydroxy-4-(40-chlorophenyl)butan-2-one 3d.10
25
Yield, 30%; ½aꢁD ¼ þ24:4 (c 0.94, CH2Cl2); enantiomeric
excess: 36%, determined by HPLC (Diacel Chiralpak AS-
H, i-PrOH/hexane 15:85), UV 254 nm, flow rate 1.0 mL/
min. R-isomer, tR 11.1 min and S-isomer, tR 13.9 min.
4.4.1.1. X-ray analysis of compound 7. The diffraction
data were obtained with graphite-monochromated Mo
Ka radiation on CrysAlis RED, Oxford CCD diffractome-
ter at 293(2) K. Standard reflection for each data set
showed no significant decrease in intensity through the
acquisition. The structure was solved by direct method
and refined by full matrix least square on F. The crystallo-
graphic calculations were performed using CrysAlis
CCD for data collection, CrysAlis RED for cell refine-
ment and data reduction. SHELXS-97 software was
used for structure solution and refinement. The struc-
ture shows the entrapment of the solvent benzene.
Crystal data: C15H19F3N2O2 M = 332.32, tetragonal,
4.5.5. (R)-4-Hydroxy-4-(20-chlorophenyl)butan-2-one 3e.10
25
Yield, 80%; ½aꢁD ¼ þ50:0 (c 1.07, CH2Cl2); enantiomeric
excess: 41%, determined by HPLC (Diacel Chiralpak AS-
H, i-PrOH/hexane 15:85), UV 262 nm, flow rate 1.0 mL/
min. R-isomer, tR 8.7 min and S-isomer, tR 9.3 min.
4.5.6. (R)-4-Hydroxy-4-(40-fluorophenyl)butan-2-one 3h.10
25
Yield, 23%; ½aꢁD ¼ þ25:9 (c 1.24, CH2Cl2); enantiomeric
excess: 37%, determined by HPLC (Diacel Chiralpak AS-
H, i-PrOH/hexane 15:85), UV 257 nm, flow rate 1.0 mL/
min. R-isomer, tR 6.5 min and S-isomer, tR 7.6 min.
˚
˚
P
4(1)2(1)2,
a = 9.454(2) A, b = 9.474(3) A, c =
3
˚
˚
42.490(13) A, b = 89.74(2)ꢁ, V = 3805.7(19) A , T =
293(2) K, l(Mo Ka) = 0.108 cmꢀ1, R = 0.0664, Rw =
0.1722, GOF = 0.752, 21565 unique reflections with
[I > 2r(I)]. The details of the crystal data have been depos-
ited with Cambridge Crystallographic Data Centre as sup-
plementary publication No. CCDC-616022.
4.5.7. (R)-4-Hydroxy-4-(40-cyanophenyl)butan-2-one 3i.10
25
Yield, 92%; ½aꢁD ¼ þ27:0 (c 0.94, CH2Cl2); enantiomeric
excess: 36%, determined by HPLC (Diacel Chiralpak AS-
H, i-PrOH/hexane 15:85), UV 254 nm, flow rate 1.0 mL/
min. R-isomer, tR 8.4 min and S-isomer, tR 15.1 min.
4.5.8. (R)-4-Hydroxy-4-phenylbutan-2-one 3j.10 Yield,
25
30%; ½aꢁD ¼ þ26:5 (c 0.40, CH2Cl2); enantiomeric excess:
4.5. General procedure for the organocatalyzed direct
asymmetric aldol reaction of acetone 2 with 4-nitrobenz-
aldehyde 1a in water
37%, determined by HPLC (Diacel Chiralpak AS-H, i-
PrOH/hexane 20:80), UV 257 nm, flow rate 1.0 mL/min.
R-isomer, tR 8.4 min and S-isomer, tR 9.9 min.
To a stirring mixture of 1a (302 mg, 2 mmol), 2 (20 mmol)
and water (3 mL), the respective organocatalyst (20
mole%) was added. The reaction was monitored by TLC
and quenched with saturated ammonium chloride solution
(15 mL) on completion and extracted with CH2Cl2
(2 · 25 mL). The organic layer was dried over anhydrous
Na2SO4 and distilled to obtain crude product. Column
chromatography of the crude on silica gel (60–120 mesh)
using mixture of ethyl acetate and hexane in varying pro-
portions as eluent, gave pure product 3a. The enantiomeric
excess of 3a was determined on HPLC using a Chiralpak
AS-H column and mixture of IPA and hexane in ratio of
15:85 as eluents.
Acknowledgements
S.S.C. thanks CSIR, India, for financial support (Research
grant No. 01/1878/03/EMR-II). D.M. thanks UGC, India,
for a senior research fellowship. The support of Dr. S. C.
Taneja and Dr. K. N. Singh is gratefully acknowledged.
The X-ray structure analysis has been done at National
Facility, IIT Bombay, Mumbai (India).
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4.5.1. (R)-4-Hydroxy-4-(40-nitrophenyl)butan-2-one 3a.10
25
Yield, 83%; ½aꢁD ¼ þ30:0 (c 1.24, CH2Cl2); enantiomeric
excess: 46%, determined by HPLC (Diacel Chiralpak AS-
H, i-PrOH/hexane 15:85), UV 254 nm, flow rate 1.0 mL/
min. R-isomer, tR 13.7 min and S-isomer, tR 19.4 min.
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7817.
25
Yield, 93%; ½aꢁD ¼ ꢀ89:0 (c 0.34, CH2Cl2); enantiomeric
excess: 62%, determined by HPLC (Diacel Chiralpak AS-

S. S. Chimni, D. Mahajan / Tetrahedron: Asymmetry 17 (2006) 2108–2119
2119
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