Protonated (S)-prolinamide derivatives-water compatible organocatalysts for direct asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2008.09.020

Protonated chiral (S)-prolinamide derivatives have been developed as water compatible highly efficient organocatalysts for a direct enantioselective aldol reaction. A simple protonated (S)-prolinamide organocatalyst prepared from l-proline and 3-nitroanil

Full text of DOI:10.1016/j.tetasy.2008.09.020

Tetrahedron: Asymmetry 19 (2008) 2276–2284
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Protonated (S)-prolinamide derivatives—water compatible organocatalysts
for direct asymmetric aldol reaction
*
Swapandeep Singh Chimni , Sarbjit Singh, Dinesh Mahajan
Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Protonated chiral (S)-prolinamide derivatives have been developed as water compatible highly efficient
organocatalysts for a direct enantioselective aldol reaction. A simple protonated (S)-prolinamide organo-
catalyst prepared from L-proline and 3-nitroaniline catalyzes the aldol reaction of unmodified ketones
and a variety of aromatic aldehydes yielding aldol product in high yield with enantioselectivities of up
to 98% and diastereoselectivity of up to >99:1.
Received 15 August 2008
Accepted 24 September 2008
Available online 22 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the substrate. In the case of amines, Spencer et al. observe that
nucleophilic catalysis in water becomes increasingly effective as
The main challenge in developing asymmetric catalysis lies in
the mimicking of natural enzymes. Designed enzyme models
should be both efficient and capable of accepting a broad range
of substrates. Aldolase enzymes1 (Types I and II) and antibodies2
are known to catalyze aldol reactions in aqueous media. In recent
the base strength of the amine catalyst is decreased.12 This can
be easily achieved by the protonation of the amine with an acid.
O
R
Br-
years, L-proline and its derivatives have been shown to mimic the
N
H
H
enzymatic activity of aldolase Type I enzymes in organic solvents,
resulting in the formation of an aldol product with high enantiose-
1
R =
lectivity.3 The
L-proline catalysis of aldol reactions in water leads to
H
HN
HN
N
Et
H
racemic products.4 This is probably due to interruption of the H-
bonding and other ionic interactions in the transition state that
are critical for any enantioselective reaction.5 Alternately, Hayashi
has obtained enantioselective aldol product with wet proline.6
However, over the last two years there have been very few reports
of organocatalysts that provide satisfactory enantio- and diastere-
oselectivities in water.7,5a Using water as a solvent and (S)-prolina-
mide derivatives as catalysts, our group has reported the first
enantioselective direct aldol reaction.8 Our interest was to design
simple proline-based organocatalysts that catalyze the aldol reac-
tion to yield the aldol product in high enantio- and diastereoselec-
tivity. The evidence gathered from studies on natural aldolases
shows that the active center in the aldolase enzyme is the proton-
NH
NH
(R
)
1a
1c
1b
1e
1d
H
N
(R)
H
H
N
H
HN
Me
H
N
Me
Me N
Me
(S
)
H
1g
1f
1h
1i
1j
F
NH
NH
NH
NH
NH
ated e-amino group of a lysine residue that lies in a hydrophobic
pocket composed of long chain peptides with perturbed pKa.9 We
envisaged that protonated prolinamides,8 containing aromatic
rings, will act as ideal models for an aldolase Type I enzyme, where
on the one hand the aromatic group provides suitable hydrophobic
interactions,10 and on the otherhand, the amidic –NH group pro-
vides appropriate hydrogen bonding11 for suitable orientation of
NO2
F
Cl
Br
NO2
1k
1l
1m
1o
1n
NH
N
NO2
N
N
N(Me)2
* Corresponding author. Tel.: +91 183 2258802 to 09; fax: +91 183 2258820.
O
E-mail
addresses:
sschimni@yahoo.com,
sschimni.chem@gndu.ac.in
1s
1q
1r
1t
1p
(S. S. Chimni).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.020

S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
2277
Herein, we report the use of protonated (S)-prolinamide deriva-
tives as water compatible organocatalysts for direct aldol reaction
of ketones with aromatic aldehydes.
Catalyst 1p, with an electron-withdrawing group at the ortho-
position, affords 4a with lower enantio- and diastereoselectivity
(Table 1, entry 16). This is perhaps due to the steric hindrance
caused by the nitro group in the transition state. The catalysts 1j,
1q, 1r, 1s, and 1t provide 4a with moderate enantioselectivity
(Table 1, entries 10 and 17–20).
2. Result and discussion
The two catalysts 1c and 1o that provided 4a in 90% ee were
selected for further optimization of the reaction conditions. Cata-
lyst 1c has a naphthyl as a hydrophobic group, whereas 1o has
3-nitrophenyl as an electron-deficient hydrophobic group. In order
to determine if the change in the volume of water has any effect on
their catalytic efficiency, we initially performed a direct aldol reac-
tion using catalyst 1c, because it has a large hydrophobic group.
The results indicate that while the volume of water does not have
much effect on the enantiomeric excess, it does affect the diaste-
reomeric excess. The highest diastereomeric excess was obtained
by using 2.5 mL of water (Table 2), and thus, all further reactions
were performed using this volume of water.
In our preliminary study, the aldol reaction of cyclohexanone 2
and 4-nitrobenzaldehyde 3a was carried out with catalyst 1a using
water as a solvent. The aldol product 4a was isolated with a yield of
81%, a diastereomeric ratio of 95:5 (anti:syn) and ee of 88% for the
major anti-product (Table 1, entry 1). Initially, the reaction mixture
was biphasic, consisting of an upper thin layer of cyclohexanone
and a lower bulky layer of water containing dissolved protonated
catalyst, as well as undissolved aldehyde at the bottom. After a
few hours of stirring, an organic layer appeared at the bottom of
the reaction vessel, which upon investigation was found to consist
of product 4a. The screening of other catalysts for the aldol reac-
tion provided 4a in moderate to good diastereoselectivity and
enantioselectivity. Increasing the hydrophobicity of the catalyst,
via introduction of the naphthyl group as in 1c, had a very minor
effect on the enantioselectivity (Table 1, entry 3). The introduction
of a CH2 spacer between the aromatic group and nitrogen gave
lower diastereoselectivities and enantioselectivities (Table 1, en-
tries 2 and 4). To explore the possibility of a match and mismatch
effect of the stereogenic centers on the catalysts, diastereomeric
prolinamide catalysts 1f, 1g, and 1h were prepared. However, they
yielded 4a with lower diastereoselectivities and moderate enanti-
oselectivities (Table 1, entries 6–8). Moderate enantio- and diaste-
reoselectivities were observed with catalysts 1e and 1i (Table 1,
entries 5 and 9). The catalysts 1k to 1o, having an electron-with-
drawing group in the aromatic ring, afford 4a with good enantio-
selectivity on the one hand, but moderate diastereoselectivity on
the other (Table 1, entries 11–15).
Table 2
Variation of amount of water using catalyst 1ca
Entry
Water (mL)
Time (h)
Yieldb (%)
drc anti:syn
eed (%)
1
2
3
4
5
0.1
0.5
1.5
2.5
5
30
30
30
30
30
88
81
84
89
87
79:21
85:15
85:15
93:7
87
87
87
88
79
87:13
a
Reaction conditions: 2.5 mL of water, 5 mmol of ketone, 1 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yields determined after chromatographic purifications.
Diastereomeric excess determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
c
d
We further planned to vary the amount of ketone because for
the development of an eco-friendly process, it is prudent to use
stoichiometric amounts of reactants. A high enantiomeric excess
of 93% was obtained using 5 equiv of cyclohexanone (Table 3, entry
2), while using a lower amount led to loss of enantioselectivity as
well as decrease in the yield of 4a. These conditions were then
taken as the standard for all subsequent cross aldol reactions.
Table 1
Screening of various organocatalysts for direct aldol reactiona
O
OH
O
O
1(20 mol%)
H
+
Water
Table 3
Variation in amount of cyclohexanone using catalyst 1ca
NO2
eed (%)
O2N
3a
4a
2
Entry
2 (mmol)
Time (h)
Yieldb (%)
drc anti:syn
eed (%)
Entry
Catalyst
Time (h)
Yieldb (%)
drc anti:syn
1
2
3
4
5
10
5
3
2
1.5
30
30
41
41
41
84
85
67
60
62
85:15
88:12
93:7
84:16
81:19
91
93
82
80
75
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1b
1c
1d
1e
1f
1g
1h
1i
29
30
72
72
48
50
17
17
29
27
19
19
19
24
18
24
14
20
22
24
81
81
79
81
76
70
87
85
82
83
90
88
89
89
81
73
89
88
85
81
95:5
90:10
93:7
90:10
69:31
87:13
78:22
83:17
92:8
85:15
78:22
80:20
75:25
82:12
87:13
82:18
71:29
69:31
76:24
73:27
88
85
90
74
81
85
83
76
67
83
87
87
82
89
90
41
75
76
84
66
a
Reaction conditions: 2.5 mL of water, 5 mmol of ketone, 1 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yields determined after chromatographic purifications.
Diastereomeric excess determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
c
d
1j
1k
1l
The standard conditions of 2.5 mL of water and 5 equiv of 2
were used to perform a direct aldol reaction with 1o, since in the
initial screening this also afforded a similar level of enantioselec-
tivity as catalyst 1c (Table 1). Catalyst 1o yielded 4a in 95% ee un-
der these conditions. The enantioselectivity of 4a, using both
catalysts 1c and 1o, was observed to be higher under these condi-
tions. In addition to this, the diastereoselectivity obtained for anti-
product in the case of catalyst 1o was very good (Table 4, entry 1).
Further optimization was then carried out using 1o, as it was found
to afford 4a with the highest enantioselectivity.
1m
1n
1o
1p
1q
1r
1s
1t
a
Reaction conditions: 1 mL of water, 10 mmol of ketone, 2 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yields determined after chromatographic purifications.
Diastereomeric excess determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
c
The lowering of catalyst loading led to a slight decrease in the
enantio- as well as diastereoselectivity and also an increase in
d

2278
S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
Table 4
in CH3CN and THF provided 4a with ee of 90% and 94%, respec-
tively, but the yield of 4a was low (Table 5, entries 3 and 5). The
yield increased when performing the reaction in a THF-water mix-
ture (Table 5, entry 6). Thus, this study substantiates the superior-
ity of water as solvent for obtaining aldol product in high
enantioselectivity and diastereoselectivity using 1o as catalyst.
In order to evaluate the general scope of catalyst 1o, the aldol
reaction of 2 was performed with different aromatic aldehydes
(Table 6). The results reflect the catalytic versatility of 1o. It
catalyzes the aldol reaction of a variety of substituted aromatic
aldehydes with cyclohexanone providing aldol products 4a to 4n
in moderate to high enantioselectivity and diastereoselectivity.
The aldol reaction of 2,6-dichlorobenzaldehyde 3h provides 4h in
>99:1 diastereoselectivity and 98% ee (Table 6, entry 8). The 4-
substituted benzaldehydes 3a, 3d, 3e, 3g afford the aldol product
in ee of >90% (Table 6, entries 1, 4, 5, and 7), except for 4-bromo-
benzaldehyde 3f. The same trend is observed in 2-substituted
benzaldehydes 3j, 3k, and 3l. The reaction with benzaldehyde
3m and naphthaldehyde 3n provides lower enantioselectivity.
Effect of catalyst loading and protonation on the enantio- and diastereoselectivity of
4a using catalyst 1oa
Entry
Catalyst
(mol %)
Water
(mL)
Time
(h)
Yieldb
(%)
drc anti:syn
eed
(%)
1
2
3
20
10
5
1
2.5
2.5
2.5
2.5
16.5
2.5
2.5
2.5
—
24
45
49
4 days
4 days
24
24
7
38
7
92
87
86
82
81
87
43
73
72
79
94:6
86:14
82:18
79:21
84:16
86:14
94:6
70:30
58:42
73:27
95
94
92
92
90
94
95
38
55
58
4
5f
6g
7h
8e
9
1
20 (C1)
20 (C2)
20
20
20
10e
—
a
Reaction conditions: 2.5 mL of water, 5 mmol of ketone, 1 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yield determined after chromatographic purification.
Diastereomeric excess determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
Reaction was performed without protonation of the catalyst.
Reaction was performed using 1 g of 4-nitrobenzaldehyde.
The reaction was performed using recovered catalyst (Cycle 1).
The reaction was performed using recovered catalyst from first cycle and
c
d
e
f
g
h
Table 6
0.5 mmol of 3a (Cycle 2).
Direct aldol reaction of different aldehydes using catalyst 1oa
O
O
O
OH
Cat. 1o (20 mol%)
the reaction time (Table 4, entries 2 and 3). Interestingly, enantio-
selectivity of 92% and yield of 82% were observed by using 1 mol %
of this catalyst (Table 4, entry 4). One of the most intriguing as-
pects of developing an industrial process is the scaling up of the
reaction and recyclability of the catalysts. A gram scale reaction
was performed using 1 g of aldehyde and employing only 1 mol %
of catalyst 1o. This provided 4a in 81% yield and 90% ee (Table 4,
entry 5). No loss in the activity of the catalysts was observed even
after two cycles. The product obtained exhibited nearly similar
enantioselectivity (Table 4, entries 6 and 7).
In order to determine the role of water, a reaction was per-
formed in the absence of water under solvent-free conditions. This
resulted in longer reaction time, and afforded 4a with low diaste-
reo- and enantioselectivity (Table 4, entry 9). On the other hand,
the reaction was very fast when using deprotonated catalyst 1k
in both water and solvent-free conditions, but 4a obtained exhib-
ited poor enantio- and diastereoselectivity (Table 4, entries 8 and
10). Furthermore, the catalytic efficiency of 1o was also deter-
mined in organic solvents (Table 5). The aldol reaction performed
+
water
R
R
4
3
2
Entry
ArCHO
Time (h)
Yieldb (%)
drc anti:syn
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4-NO2C6H4 3a
3-NO2C6H4 3b
2-NO2C6H4 3c
4-FC6H4 3d
4-ClC6H4 3e
4-BrC6H4 3f
4-CNC6H4 3g
2,6-Cl2C6H3 3h
3,4-Cl2C6H4 3i
2-FC6H4 3j
2-ClC6H4 3k
2-BrC6H4 3l
C6H5 3m
24
24
30
24
24
24
24
24
24
24
24
24
24
27
92
83
86
61
73
61
71
89
82
71
69
73
62
35
94:6
88:12
92:8
93:7
92:8
95
86
94
92
95
87
90
98
84
93
91
82
82
79
93:7
88:12
>99:1
72:28
87:13
98:2
86:14
87:13
93:7
2-Naph 3n
a
Reaction conditions: 2.5 mL of water, 5 mmol of ketone, 1 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yields determined after chromatographic purification.
Diastereomeric excess determined by NMR of the crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
c
d
Table 5
Effect of organic solvents on the enantio- and diastereoselectivity of 4a using catalyst
1oa
Finally, a number of ketones were also screened using catalyst
1o providing aldol products in moderate to excellent enantioselec-
tivities using optimized conditions (Table 7). Cyclic ketones having
a six membered ring provide higher enantioselectivity of the aldol
product as compared to five membered cyclic ketones (Table 7). In
case of acyclic ketones, moderate enantioselectivity and yield were
obtained along with prolonged reaction time (Table 7, entries 9
and 10).
The stereochemistry of the aldol reaction can be rationalized
through the proposed transition state13 (Fig. 2). Here the enamine
attacks the aldehyde on the re face and leads to the formation of
the favored anti-diastereomer as the major product. The carbonyl
group of the aldehyde is activated by H-bonding with the amide
N–H. The role of the amide N–H in the hydrogen bonding is con-
firmed by the increase in the rate of reaction and also by the
enantioselectivity of the product in the case of catalysts with an
electron-withdrawing group on the aromatic ring. Further, we be-
lieve that hydrophobic interactions14 also play an important role in
O
OH
O
O
Cat. 1o (20 mol%)
H
+
Solvent
NO2
O2N
4a
2
3a
Entry
Solvent
Time (h)
Yieldb (%)
drc anti:syn
eed (%)
1
2
3
4
5
6
7
DMSO
DMF
CH3CN
Hexane
THF
24
24
24
24
24
24
24
—
—
51
—
73
80
—
—
—
93:7
—
92:8
94:6
—
—
—
90
—
94
94
—
THF:Water (1:1)
MeOH
a
Reaction conditions: 2.5 mL of water, 5 mmol of ketone, 1 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yields determined after chromatographic purification.
Diastereomeric excess determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
c
d

S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
2279
Table 7
Direct aldol reaction of different ketones using catalyst 1oa
O
O
O
OH
Cat. 1o (20 mol%)
+
water
R
Aldol product
R
3
5-14
Entry
1
Time (h)
24
Yieldb
88
drc anti:syn
eed (%)
O
OH
—
—
95
Figure 1. X-ray structure of catalyst 1o.
NO2
+ isomers
OH
5
O
NO2
2
24
85
95
O
N
H
O2N
+ isomers
(S)
6
N
O
O
OH
H
3
24
24
80
70
—
97
91
Cl
+ isomers
OH
7
Figure 2. Plausible transition state.
O
4e
85:15
providing rigidity to the transition state, and this in turn increases
the enantioselectivity of the aldol product.
NO2
O
O
Catalyst 1o has an orthorhombic crystal lattice as shown by the
X-ray crystal structure (Fig. 1).15 There are two NH–Br hydrogen
bonds between bromine ion and the pyrrolidine NH of successively
stacked molecules (2.358 Å and 2.704 Å) and one amidic NH–Br
hydrogen bond (2.681 Å) with the molecule stacked in the adjacent
molecular stacking. The m-nitro group on the aromatic ring is posi-
tioned on the same side as the carbonyl oxygen; having an intra-
molecular CH–O distance of 2.288 Å between the ortho H atom
and the carbonyl group. The aromatic ring was placed nearly
orthogonal to the pyrrolidine ring.
8
O
OH
5e
24
26
90
69
—
92
90
NO2
+ isomers
9
O
O
O
OH
6
70:30
O2N
3. Conclusion
10
OH
In summation, we have successfully demonstrated that very
simple protonated (S)-prolinamide derivatives efficiently catalyze
aldol reaction in water. The methodology developed is very simple,
environmentally benign, and highly enantioselective. We believe
that our findings will open up new avenues for the design of struc-
turally simple organocatalysts that would be highly effective under
aqueous reaction conditions.
7
8
24
24
78
74
52:48
56:44
80
73
11
NO2
OH
NO2
12
O
OH
4. Experimental
9f
3 days
3 days
63
21
—
50
48
4.1. General methods
NO2
13
O
OH
NMR spectra were obtained at 300 MHz (Jeol AL-300) using
either CDCl3 or D2O as solvents with Me4Si in CDCl3 as the internal
standard. The chemical shifts are reported in d values relative to
TMS and coupling constants (J) are expressed in hertz. Spectral pat-
terns are designated as s = singlet; d = doublet; dd = doublet of
doublets; q = quartet; t = triplet; br = broad; m = multiplet. When
necessary, assignments were aided by DEPT-135 and decoupling
experiments. Analytical thin-layer chromatography (TLC) was per-
formed 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
10
50:50
NO2
14
a
Reaction conditions: 2.5 mL of water, 5 mmol of ketone, 1 mmol of aldehyde,
20 mol % catalyst, 27 °C.
b
Yields determined after chromatographic purification.
Diastereomeric excess determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral HPLC for anti-diastereomer.
c
d
e
Mixture of water and THF (1:1) was used as solvent.
Linear and branched regioisomers17 were formed in a ratio of 2:3.
f

2280
S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
sulfate as binder and various combinations of ethyl acetate and
hexane were used as eluents. Visualization of the spots was
accomplished by exposing to UV light or iodine vapors. Column
chromatography was performed on 60–120 mesh silica (Spectro-
chem, India) using 1–8% methanol in dichloromethane and
mixture of hexane and ethylacetate as eluents. Organic substrates,
aryl, and alkyl amines were obtained from either Aldrich or S.d.
1H, CH), 7.12–7.15 (d, 2H, J = 9 Hz, ArH), 7.21–7.24 (d, 2H,
J = 8.7 Hz, ArH); 13C NMR (D2O, 300 MHz): d 24.5, 30.5, 47.3, 60.8,
118.4, 123.3, 132.5, 136.1, 168.3.
4.2.6. (S)-2-(40-Nitrophenylcarbamoyl)pyrrolidinium
bromide 1n
Yield, 47%, light pale yellow solid; mp: 187–189 °C; Rf 0.2
(methanol/chloroform, 1:99); MS (m/z) FAB: 236 (M+);
fine-chem. Ltd., India and
L-proline, Dicyclohexylcarbodiimide
½
a 2D0
ꢁ
¼ ꢂ36:3 (c 0.71, MeOH); 1H NMR (D2O, 300 MHz): d 1.89–
and benzylchloroformate (Cbz) as 50% solution in toluene were
procured from Spectrochem, India and used as received.
2.10 (m, 3H, CH2), 2.32–2.44 (m, 1H, CH2), 3.21–3.38 (m, 2H,
CH2), 4.34–4.39 (m, 1H, CH), 7.50–7.55 (m, 2H, ArH), 8.04–8.09
(m, 2H, ArH); 13C DEPT NMR (D2O, 300 MHz): d 24.4 (ꢂve), 30.2
(ꢂve), 47.2 (ꢂve), 61 (+ve), 120.8 (+ve), 125.6 (+ve), 143.5, 168.9;
Anal. Calcd for C11H14O3N3Br: C, 41.79; H, 4.46; N, 13.29. Found
C, 42.33; H, 4.82; N, 13.32.
4.2. General procedure for the synthesis of catalysts 1a–m
Catalysts were synthesized by a standard procedure reported
earlier8b and the spectroscopic data were similar to those reported.
The experimental data for the new catalysts are given below.
4.2.7. (S)-2-(30-Nitrophenylcarbamoyl)pyrrolidinium
bromide 1o
4.2.1. (S)-2-(10-Naphthmethylcarbamoyl)pyrrolidinium
bromide 1d
Yield, 52%; light pale yellow solid, mp: 180–182 °C; Rf 0.2
(methanol/chloroform, 1:99); MS (m/z) FAB: 236 (M+);
Yield, 52%; dark brown solid; mp: 190–192 °C; Rf 0.3 (metha-
nol/chloroform, 4:96); MS (m/z) FAB: 255 (M+); ½a D20
¼ ꢂ22:6 (c
ꢁ
½
a 2D0
ꢁ
¼ ꢂ38:1 (c 0.94, MeOH); 1H NMR (D2O, 300 MHz): d 2.10–
0.41, MeOH); 1H NMR (D2O, 300 MHz): d 1.63–1.81 (m, 3H, CH2),
2.02–2.11 (m, 1H, CH2), 3.09–3.20 (m, 2H, CH2), 4.07–4.12 (m,
1H, CH2), 4.39–4.44 (d, 1H, J = 15 Hz, CH), 7.16–7.34 (m, 4H,
ArH), 7.56–7.65 (m, 3H, ArH); 13C NMR (D2O, 300 MHz): d 24.3,
30.4, 41.8, 47.1, 60.3, 123.5, 126.6, 127.1, 128.8, 129.2, 131.1,
133, 134, 168.8, 169.4.
2.32 (m, 3H, CH2), 2.50–2.62 (m, 1H, CH2), 3.44–3.58 (m, 2H,
CH2), 4.56–4.61 (m, 1H, CH), 7.59–7.64 (m, 1H, ArH), 7.78–7.81
(m, 1H, ArH), 8.05–8.08 (m, 1H, ArH), 8.40–8.41 (m, 1H, ArH);
13C NMR (D2O, 300 MHz): d 26.2, 32.1, 49.1, 62.7, 117.6, 122.4,
129.2, 132.5, 139.9, 150.2, 170.5; Anal. Calcd for C11H14O3N3Br: C,
41.79; H, 4.46; N, 13.29. Found: C, 41.50; H, 4.73; N, 13.18.
4.2.2. (S)-2-(40-Fluorobenzylcarbamoyl)pyrrolidinium
bromide 1j
4.2.8. (S)-2-(20-Nitrophenylcarbamoyl)pyrrolidinium
bromide 1p
Yield, 60%; light brown liquid; Rf 0.3 (methanol/chloroform,
Yield, 40%; dark brown solid; mp: 181–183 °C; Rf 0.2 (metha-
5:95); MS (m/z) FAB: 223 (M+); ½a D20
ꢁ
¼ ꢂ22:4 (c 0.49, MeOH); 1H
nol/chloroform, 5:95); MS (m/z) FAB: 236 (M+); ½a D20
¼ ꢂ29:7 (c
ꢁ
0.21, MeOH); 1H NMR (D2O, 300 MHz): d 1.85–2.11 (m, 3H, CH2),
2.34–2.46 (m, 1H, CH2), 3.20–3.35 (m, 2H, CH2), 4.46–4.52 (m,
1H, CH), 7.21–7.26 (t, 1H, J = 7.5 Hz, ArH), 7.46–7.55 (m, 2H,
ArH), 7.83–7.85 (d, 1H, J = 6 Hz, ArH); 13C NMR (D2O, 300 MHz):
d 24.4, 30.1, 47.3, 60.9, 126.1, 127, 127.9, 129.9, 135.7, 142.6,
169.4.
NMR (D2O, 300 MHz): d 2.01–2.14 (m, 3H, CH2), 2.45–2.54 (m,
1H, CH2), 3.38–3.48 (m, 2H, CH2), 4.34–4.49 (m, 3H, CH and CH2),
7.10–7.16 (m, 2H, ArH), 7.32–7.36 (m, 2H, ArH); 13C NMR (D2O,
300 MHz): 24.4, 30.41, 43.2, 50, 60.4, 115.9, 116.1, 129.7, 129.8,
133.9, 170; Anal. Calcd for C12H16ON2BrF: C, 47.54; H, 5.32; N,
9.24. Found: C, 47.56; H, 6.05; N, 9.63.
4.2.3. (S)-2-(40-Fluorophenylcarbamoyl)pyrrolidinium
bromide 1k
4.2.9. (S)-2-[30-(N,N-Dimethylamonium)propyl
carbamoyl]prrolidinium dibromide 1q
Yield, 57%, brown solid; mp: 177–179 °C; Rf 0.2 (methanol/chlo-
Yield, 57%, light brown solid; mp: 192–194 °C; Rf 0.4 (methanol/
roform, 2:98); MS (m/z) FAB: 209 (M+); ½a D20
¼ ꢂ38:8 (c 1.0,
ꢁ
chloroform, 5:95); MS (m/z) FAB: 197 (M+);
½
a 2D0
ꢁ
¼ ꢂ27:05
MeOH); 1H NMR (D2O, 300 MHz): d 2.14–2.32 (m, 3H, CH2),
2.62–2.76 (m, 1H, CH2), 3.52–3.68 (m, 2H, CH2), 4.62–4.70 (m,
1H, CH), 7.16–7.23 (m, 2H, ArH), 7.49–7.56 (m, 2H, ArH); 13C
NMR (D2O, 300 MHz): d 26.4, 32.4, 49.2, 62.6, 118, 118.2, 125.6,
125.7, 134.8, 170.5.
(c 0.32, MeOH); 1H NMR (D2O, 300 MHz): d 0.94–1.14 (m, 6H,
CH3), 1.38–1.90 (m, 8H, CH2), 2.10–2.32 (m, 1H, CH2), 3.10–3.24
(m, 2H, CH2), 3.42–3.43 (m, 1H, CH2), 4.08–4.12 (m, 1H, CH); 13C
NMR (D2O, 300 MHz): d 24.5, 24.9, 25.5, 30.7, 32.4, 47.2, 50.1,
60.4, 168.9.
4.2.4. (S)-2-(40-Chlorophenylcarbamoyl)pyrrolidinium
bromide 1l
4.3. General procedure for the enantioselective aldol reaction
Yield, 60%, white solid; mp: 183–185 °C; Rf 0.2 (methanol/chlo-
To a solution of water (2.5 mL) and catalyst (0.2 mmol), cyclo-
hexanone (5 mmol) was added at 27 °C, and the mixture was
allowed to stir for 5 min followed by addition of aldehyde
(1 mmol). The reaction mixture was stirred for 9–48 h and was
monitored with TLC at regular intervals. On completion of the reac-
tion, water (5 mL) was added to it and the resulting mixture was
extracted with dichloromethane (3 ꢀ 10 mL). The organic layer
was separated, dried over anhydrous sodium sulfate, filtered, and
evaporated to obtain crude aldol product. The 1H NMR of the crude
reaction mixture was recorded to determine the diastereomeric
excess. The column chromatography on silica gel (mesh 60–120)
gave pure aldol product. The HPLC of the pure aldol product was
performed using Diacel Chiralpak AS-H, OD-H, and AD-H columns
using mixture of hexane–isopropanol as eluting solvents.
roform, 2:98); MS (m/z) FAB: 225(M+); ½a D20
¼ ꢂ36:4 (c 1.0, MeOH);
ꢁ
1H NMR (D2O, 300 MHz): d 1.82–1.96 (m, 3H, CH2), 2.33–2.41 (m,
1H, CH2), 3.25–3.33 (m, 2H, CH2), 4.36–4.40 (m, 1H, CH), 6.99–
7.02 (d, 2H, J = 8.7 Hz, ArH), 7.16–7.18 (d, 2H, J = 8.4 Hz, ArH); 13C
NMR (D2O, 300 MHz): d 24.5, 30.7, 47.4, 60.8, 122.8, 129.5, 130.4,
135.7, 168.
4.2.5. (S)-2-(40-Bromophenylcarbamoyl)pyrrolidinium
bromide 1m
Yield, 42%, brown solid; mp: 188–189 °C; Rf 0.2 (methanol/chlo-
roform, 2:98); MS (m/z) FAB: 270 (M+); ½a D20
¼ ꢂ37:4 (c 1.0,
ꢁ
MeOH); 1H NMR (D2O, 300 MHz): d 1.80–2.01 (m, 3H, CH2),
2.25–2.42 (m, 1H, CH2), 3.20–3.35 (m, 2H, CH2), 4.30–4.38 (m,

S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
2281
4.3.1. 2-[10-Hydroxy-10-(400-nitrophenyl)methyl] cyclohexan-1-
one16a 4a
OH (syn)), 3.91 (bs, 1H, OH (anti)), 4.71–4.74 (d, 1H, J = 9 Hz, CH
(anti)), 5.33 (s, 1H, CH (syn)), 7.20–7.30 (m, 4H, ArH); 13C NMR
(CDCl3, 300 MHz): d 24.6, 24.8, 25.9, 27.7, 27.9, 30.7, 42.6, 57.0,
57.3, 70.1, 74.1, 127.1, 128.2, 128.3, 128.5, 132.6, 133.5, 139.4,
140, 214.6, 215.3.
Yield: 92%; anti/syn = 94:6; enantiomeric excess: 95% deter-
mined by HPLC (Daicel Chiralpak AS-H, hexane/i-PrOH 85:15; flow
rate 0.3 mL minꢂ1, k = 254 nm; tR (syn, major) = 43.86 min, tR (anti,
major) = 48.23, tR (anti, minor) = 59.0 min, tR (syn, minor) = 66.56
min; 1H NMR (CDCl3, 300 MHz): d 1.53–1.85 (m, 4H, CH2), 2.05–
2.13 (m, 1H, CH2), 2.33–2.56 (m, 4H, CH2 and CH), 3.90–4.20 (br
s, 1H, OH), 4.85–4.88 (d, 1H, J = 9 Hz, CH (anti)), 5.48 (s, 1H, CH
(syn)), 7.45–7.49 (m, 2H, ArH), 8.15–8.19 (m, 2H, ArH); 13C NMR
(CDCl3, 300 MHz): d 24.5, 24.6, 25.8, 27.5, 27.6, 30.6, 42.4, 42.5,
56.7, 57.0, 69.9, 73.8, 123.3, 123.4, 126.5, 127.8, 147.4, 148.3,
149.2, 213.9, 214.6.
4.3.6. 2-[10-Hydroxy-10-(400-bromophenyl)methyl] cyclohexan-
1-one16a 4f
Yield: 61%; anti/syn = 93:7; enantiomeric excess: 87% deter-
mined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH 90:10; flow
rate 0.3 mL/min; k = 222 nm; tR (syn, major) = 30.0 min, tR (syn,
minor) = 35.5, tR (anti, major) = 46.3 min, tR (anti, minor) = 53.8
min; 1H NMR (CDCl3, 300 MHz): d 1.50–1.87 (m, 5H, CH2), 2.05–
2.11 (m, 1H, CH2), 2.33–2.57 (m, 3H, CH2 and CH), 3.05 (br s, 1H,
OH (syn), 3.93 (bs, 1H, OH (anti)), 4.70–4.73 (d, 1H, J = 9 Hz, CH
(anti)), 5.30 (br s, 1H, CH (syn)), 7.14–7.18 (m, 2H, ArH), 7.42–
7.46 (m, 2H, ArH).
4.3.2. 2-[10-(Hydroxy-10-(300-nitrophenyl)methyl] cyclohexan-1-
one16a 4b
Yield: 83%; anti/syn = 88:12; enantiomeric excess: 86% deter-
mined by HPLC (Diacel Chiralpak AD-H, hexane/i-PrOH 95:5, flow
rate 0.8 mL/min; k = 254 nm; tR (syn, major) = 35.09 min, tR = (syn,
minor) = 40.14 min, tR (anti, major) = 43.79 min, tR (anti, minor) =
56.53 min; 1H NMR (CDCl3, 300 MHz): d 1.57–1.74 (m, 5H, CH2),
1.98–2.10 (m, 1H, CH2), 2.39–2.46 (m, 2H, CH2), 2.61–2.70 (m,
1H, CH), 3.20–3.32 (br s, 1H, OH (syn)), 4.13–4.30 (br s, 1H, OH
(anti)), 4.92–4.95 (d, 1H, J = 9 Hz, CH (anti)), 5.47–5.48 (d, 1H,
J = 2.4 Hz, CH (syn)), 7.49–7.56 (m, 1H, ArH), 7.69–7.70 (m, 1H,
ArH), 8.06–8.22 (m, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d 24.5,
25.8, 27.5, 27.7, 30.6, 42.5, 56.6, 57.0, 69.7, 73.9, 120.8, 122,
122.7, 129, 129.2, 131.9, 133.1, 143.2, 148.1, 214.7.
4.3.7. 2-[10-Hydroxy-10-(400-cyanophenyl)methyl] cyclohexan-1-
one16a 4g
Yield: 71%; anti/syn = 88:12; enantiomeric excess: 90% deter-
mined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH 90:10; flow
rate 0.3 mL/min, k = 234 nm; tR (syn, major) = 53.2 min, tR (syn,
minor) = 62.9, tR (anti, major) = 72.7 min, tR (anti, minor) = 91.6 -
min; 1H NMR (CDCl3, 300 MHz): d 1.25–1.84 (m, 5H, CH2), 2.08–
2.13 (m, 1H, CH2), 2.28–2.58 (m, 3H, CH2 and CH) 3.12 (br s, 1H,
OH (syn)), 3.95 (br s, 1H, OH (anti)), 4.78–4.81 (d, 1H, J = 9 Hz, CH
(anti)), 5.39 (s, 1H, CH (syn)), 7.39–7.40 (m, 2H, ArH), 7.60–7.63
(m, 2H, ArH). 13C NMR (CDCl3, 300 MHz): d 24.5, 25.7, 27.5, 30.6,
42.5, 56.6, 57.0, 70.74, 111.5, 118.7, 126.4, 127.6, 128.6, 130.4,
132, 146.3, 147, 213.9, 214.7.
4.3.3. 2-[10-Hydroxy-10-(200-nitrophenyl)methyl] cyclohexan-1-
one16a 4c
Yield: 86%; anti/syn = 92:8; enantiomeric excess: 94% deter-
mined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH 95:5; flow
rate 0.3 mL/min; k = 254 nm; tR (anti, major) = 65.04 min, tR (anti,
minor) = 69.86 min; 1H NMR (CDCl3, 300 MHz): d 1.51–1.82 (m,
5H, CH2), 1.91–2.20 (m, 1H, CH2), 2.25–2.50 (m, 2H, CH2), 2.70–
2.80 (m, 1H, CH), 4.20–4.89 (br s, 1H, OH), 5.42–5.45 (d, 1H,
J = 3 Hz, CH (anti)), 5.92 (s, 1H, CH (syn)), 7.30–7.45 (m, 1H, ArH),
7.55–7.68 (m, 1H, ArH), 7.70–7.82 (m, 2H, ArH); 13C NMR (CDCl3,
300 MHz): d 24.6, 26.3, 27.6, 29.5, 30.9, 42.4, 42.6, 54.7, 57.1,
61.4, 66.4, 69.5, 123.9, 124.3, 128.3, 128.9, 129.4, 132.9, 133.6,
133.9, 136.4, 137, 146.9, 148.6, 213.7, 214.8.
4.3.8. 2-[10-Hydroxy-10-(200,600-dichlorophenyl)methyl]
cyclohexan-1-one16a 4h
Yield: 89%; anti/syn = >99:1; enantiomeric excess: 98% deter-
mined by HPLC (Diacel Chiralpak AS-H; hexane/i-PrOH 95:5; flow
rate 0.5 mL/min; k = 220 nm; tR (anti, minor) = 20.69 min, tR (anti,
major) = 25.03 min; 1H NMR (CDCl3, 300 MHz) d 1.25–1.45 (m,
1H, CH2), 1.46–1.86 (m, 4H, CH2), 2.05–2.15 (m, 1H, CH2), 2.30–
2.58 (m, 2H, CH2), 3.43–3.54 (m, 1H, CH), 3.68–3.69 (d, 1H,
J = 4.2 Hz OH), 5.80–5.87 (m, 1H, CHOH), 7.12–7.17 (m, 1H, ArH),
7.26–7.32 (m, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d 24.5, 27.4,
29.7, 42.2, 53.4, 70.3, 129.1, 134.5, 135.4, 214.1.
4.3.4. 2-[10-Hydroxy-10-(400-fluorophenyl)methyl] cyclohexan-1-
one7f 4d
4.3.9. 2-[10-Hydroxy-10-(300,400-dichlorophenyl)methyl]
cyclohexan-1-one 4i
Yield: 61%; anti/syn = 93:7; enantiomeric excess: 92% deter-
mined by HPLC (Diacel Chiralpak AD-H, hexane/i-PrOH 90:10; flow
rate 0.3 mL/min; k = 208 nm; tR (syn, major) = 27.9 min, tR (syn,
minor) = 31.7, tR (anti, major) = 40.8 min, tR (anti, minor) = 44.9 -
min; 1H NMR (CDCl3, 300 MHz): d 1.41–1.87 (m, 5H, CH2), 1.91–
2.21 (m, 1H, CH2), 2.26–2.49 (m, 3H, CH2 and CH), 3.01–3.20 (br
s, 1H, OH (syn)), 3.88–3.92 (br s, 1H, OH (anti)), 4.70–4.73 (d, 1H,
J = 9 Hz, CH (anti)), 5.29 (s, 1H, CH (syn)), 6.96–7.00 (m, 2H, ArH),
7.20–7.23 (br s, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d 24.6,
24.8, 26.0, 27.7, 27.9, 30.7, 42.6, 53.4, 57.1, 57.4, 70.1, 74.1,
114.8, 115.3, 127.2, 128.6, 214.7.
Yield: 82%; anti/syn = 72:28; enantiomeric excess: 84% deter-
mined by HPLC(Diacel Chiralpak AD-H; hexane/i-PrOH 90:10; flow
rate 0.3 mL/min; k = 215 nm; tR (anti, major) = 36.45 min, tR (anti,
minor) = 38.76 min; 1H NMR (CDCl3, 300 MHz) d 1.30–1.45 (m,
1H, CH2), 1.52–1.98 (m, 5H, CH2), 2.15–2.18 (m, 1H, CH2), 2.30–
2.60 (m, 2H, CH and CH2), 3.23 (s, 1H, OH (syn)), 4.06 (s, 1H, OH
(anti)), 4.72–4.75 (dd, 1H, CHOH (anti), 5.32 (s, 1H, CHOH (anti)),
7.07–7.22 (m, 1H, ArH), 7.35–7.50 (m, 3H, ArH); 13C NMR (CDCl3,
300 MHz): d 24.5, 24.6, 25.8, 27.5, 27.7, 30.6, 42.5, 56.7, 57.1,
69.5, 73.6, 125, 126.3, 127.8, 128.9, 130, 130.1, 130.7, 131.6,
132.4, 141.2, 141.9, 214.1, 214.9.
4.3.5. 2-[10-Hydroxy-10-(400-chlorophenyl)methyl] cyclohexan-
1-one16a 4e
4.3.10. 2-[10-Hydroxy-10-(200-fluorophenyl)methyl] cyclohexan-
1-one16a 4j
Yield: 73%; anti/syn = 92:8; enantiomeric excess: 95% deter-
mined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH 90:10; flow
rate 0.3 mL/min; k = 224 nm; tR (syn, major) = 32.7 min, tR (syn,
minor) = 37.9, tR (anti, major) = 48.7 min, tR (anti, minor) = 55.4 -
min; 1H NMR (CDCl3, 300 MHz): d 1.55–1.87 (m, 5H, CH2), 1.98–
2.09 (m, 1H, CH2), 2.33–2.55 (m, 3H, CH2 and CH), 3.00 (br s, 1H,
Yield: 71%; anti/syn = 87:13; enantiomeric excess: 93% deter-
mined by HPLC (Diacel Chiralpak AS-H; hexane/i-PrOH 90:10; flow
rate 0.8 mL/min; k = 215 nm; tR (anti, major) = 15.63 min, tR (anti,
minor) = 17.05 min; 1H NMR (CDCl3, 300 MHz): d 1.37–1.92 (m,
5H, CH2), 2.07–2.20 (m, 1H, CH2), 2.25–2.50 (m, 2H, CH2), 2.55–
2.73 (m, 1H, CH)), 3.82–4.08 (br s, 1H, OH), 5.14–5.16 (d, 1H,

2282
S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
J = 6 Hz, CH (anti)), 6.96–7.02 (t, 1H, J = 9 Hz, ArH), 7.12–7.28 (m,
2H, ArH), 7.43–7.48 (t, 1H, J = 7.5 Hz, ArH).
18.0, 18.2, 20.8, 21, 26.5, 30.9, 31.3, 32.6, 32.9, 33.4, 34.6, 35.4,
35.9, 38, 38.4, 40.6, 41.5, 52, 53, 53.3, 55.6, 69.7, 70.2, 73.8,
123.2, 123.3, 123.4, 126.4, 127.6, 127.7, 146.8, 147.4, 148.5,
149.2, 213.9, 214.6.
4.3.11. 2-[10-Hydroxy-10-(200-chlorophenyl)methyl] cyclohexan-
1-one16d 4k
4.3.16. 2-[10-Hydroxy-10-(200-nitrophenyl)methyl]-4-
methylcyclohexan-1-one 616b
Yield: 69%; anti/syn = 98:2; enantiomeric excess: 91% deter-
mined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH 90:10; flow
rate 0.3 mL/min; k = 225 nm; tR (syn, major) = 11.08 min, tR (syn,
minor) = 12.10, (anti, major) = 19.35 min, tR (anti, minor) = 21.89
min; 1H NMR (CDCl3, 300 MHz): d 1.55–1.82 (m, 5H, CH2), 2.07–
2.11 (m, 1H, CH2), 2.27–2.48 (m, 2H, CH2), 2.59–2.62 (m, 1H, CH),
3.96 (br s, 1H, OH), 5.29–5.31 (d, 1H, J = 6 Hz, CH (anti)), 5.67 (s,
1H, CH (syn)), 7.17–7.32 (m, 3H, ArH), 7.51–7.54 (d, 1H, ArH). 13C
NMR (CDCl3, 300 MHz): d 24.7, 25.8, 27.8, 42.5, 53.5, 67.6, 126.5,
128.1, 128.4, 129.1, 130.7, 138.5, 214.7.
Yield: 85%, enantiomeric excess: 95% of major diastereomer
determined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH
80:20; flow rate 0.8 mL/min; k = 225 nm; tR (minor) = 9.41 min, tR
(major) = 9.98 min; 1H NMR (CDCl3, 300 MHz): d 0.81–1.10 (m
3H, CH3), 1.35–1.60 (m, 1H, CH), 1.67–2.01 (m, 3H, CH2), 2.05–
2.25 (m, 1H, CH2), 2.27–2.65 (m, 2H, CH2), 2.80–3.10 (m, 1H, CH),
5.42–5.44 (d, 0.9H, J = 6 Hz, CHOH), 5.94 (bd, 0.1H, J = 2.7 Hz,
CHOH), 7.40–7.46 (m, 1H, ArH), 7.60–7.66 (m, 1H, ArH) 7.72–
7.76 (m, 1H, ArH) 7.82–7.85 (m, 1H, ArH); 13C NMR (CDCl3,
300 MHz): d 20.2, 22.1, 23, 26.6, 29, 30.9, 34.5, 38.2, 38.4, 38.8,
40.6, 54.9, 55.9, 64.9, 69.9,74, 120.4, 121.4, 122, 122.7, 126.7,
127.3, 128.3, 129.1, 129.3, 131.5, 132.6, 143.5, 145.2, 148.1,
219.6, 222.2.
4.3.12. 2-[10-Hydroxy-10-(200-bromophenyl)methyl] cyclohexan-
1-one 4l
Yield: 73%; anti/syn = 86:14; enantiomeric excess: 82%
determined by HPLC (Diacel Chiralpak AD-H, hexane/i-PrOH
90:10; flow rate 0.3 mL/min; k = 225 nm; tR (anti, major) = 37.2
min, tR (anti, minor) = 42.9 min; 1H NMR (CDCl3, 300 MHz): d
1.25–1.86 (m, 5H, CH2), 2.07–2.11 (m, 1H, CH2), 2.27–2.48 (m,
2H, CH2), 2.60–2.69 (m, 1H, CH), 3.98 (br s, 1H, OH), 5.25–5.28
(d, 1H, J = 9 Hz, CH (anti)), 7.09–7.17 (m, 1H, ArH), 7.25–7.35 (m,
1H, ArH), 7.48–7.52 (m, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d
24.8, 27.7, 30.4, 42.6, 57.5, 72.7, 123.2, 127.7, 128.4, 129, 132.4,
140.6, 215.
4.3.17. 2-[10-Hydroxy-10-(400-chlorophenyl)methyl]-4-
methylcyclohexan-1-one 716b
Yield: 80%, enantiomeric excess 97% of major diastereomer
determined by HPLC (Diacel Chiralpak AS-H; hexane/i-PrOH
90:10; flow rate 0.8 mL/min; k = 225 nm; tR (anti, major) = 15.78
min, tR (anti, minor) = 25.20 min; 1H NMR (mixture of isomers)
(CDCl3, 300 MHz): d 0.92–1.04 (m, 3H, CH3), 1.25–1.50 (m, 2H,
CH and CH2), 1.71–1.76 (m, 1H, CH2), 1.89–2.06 (m, 2H, CH2),
2.25–2.57 (m, 2H, CH2), 2.65–2.78 (m, 1H, CH), 3.32 (br, 1H, OH),
4.72–4.75 (d, 0.8H, J = 9 Hz, CHOH), 5.31–5.34 (m, 0.2H, CHOH),
7.21–7.36 (m, 4H, ArH); 13C NMR (of three isomers) (CDCl3,
300 MHz): d 14.0, 18.5, 21.2, 26.6, 29.6, 31.5, 33.2, 33.6, 35.6,
36.1, 38.1, 41.7, 53.4, 55.9, 69.8, 74.1, 127.1, 128.2, 128.6, 129.4,
130.8, 133.6, 139.6, 215.2.
4.3.13. 2-[10-Hydroxy-10-phenylmethyl]cyclohexan-1-one16a 4m
Yield: 62%; anti/syn = 87:13; enantiomeric excess: 82% deter-
mined by HPLC (Diacel Chiralpak AD-H; hexane/i-PrOH 95:5; flow
rate 1 mL/min; k = 211 nm; tR (syn, major) = 12.1 min, tR (syn, min-
or) = 13.4, tR (anti, major) = 14.6 min, tR (anti, minor) = 16 min; 1H
NMR (CDCl3, 300 MHz): d 1.25–1.86 (m, 5H, CH2), 1.98–2.09 (m,
1H, CH2), 2.29–2.56 (m, 3H, CH2 and CH), 2.96 (br s, 1H, OH
(syn)), 3.89 (br s, 1H, OH (anti)), 4.74–4.77 (d, 1H, J = 9 Hz, CH
(anti)), 5.36 (s, 1H, CH (syn)), 7.21–7.29 (m, 5H, ArH).
4.3.18. 7-[10-Hydroxy-10-(400-nitrophenyl)methyl]-1,4-dioxa-
spiro-[4.5]decan-8-one 816a
4.3.14. 2-[10-Hydroxy-10-(naphthalene-2-yl)methyl]
cyclohexan-1-one16e 4n
Yield: 70%, anti/syn = 85:15; enantiomeric excess: 91% of anti
diastereomer determined by HPLC (Diacel Chiralpak AS-H, hex-
ane/i-PrOH 70:30, flow rate 1.0 mL/min; k = 254 nm; tR (anti, min-
or) = 10.61 min, tR (anti, major) = 14.99 min; 1H NMR (CDCl3,
300 MHz): d 1.45–1.55 (m, 1H, CH2), 1.90–2.13 (m, 3H, CH2),
2.41–2.51 (m, 1H, CH2), 2.64–2.81 (m, 1H, CH2), 2.93–3.03 (m,
1H, CH), 3.09 (d, 1H, J = 6 Hz, OH (syn)), 3.84–3.96 (m, 4H, CH2),
4.04–4.05 (d, 1H, J = 3 Hz, OH (anti)), 4.92 (d, 1H, J = 7.8 Hz, CHOH
(anti)), 5.52 (m, 1H, CHOH (syn)), 7.46–7.51 (m, 2H, ArH), 8.19–8.22
(m, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d 33.0, 34.2, 37.7, 38.4,
38.7, 52.9, 64.5, 64.6, 64.7, 69.5, 76.5, 106.7, 107.2, 123.5, 123.6,
126.4, 127.8, 148.5.
Yield: 35%; anti/syn = 93:7; enantiomeric excess: 79% deter-
mined by HPLC (Diacel Chiralpak AS-H; hexane/i-PrOH 90:10; flow
rate 0.5 mL/min; k = 225 nm; tR (syn, major) = 19.13 min, tR (syn,
minor) = 21.41, tR (anti, major) = 25.0 min, tR (anti, minor) = 27.98 -
min; 1H NMR (CDCl3, 300 MHz)
d 1.40–1.90 (m, 5H, CH2),
2.07–2.26 (m, 1H, CH2), 2.28–2.58 (m, 2H, CH2), 2.62–2.79 (m,
1H, CH), 3.20 (br s, 1H, OH (syn)), 4.06 (br s, 1H, OH (anti)), 4.94–
4.97 (d, 1H, J = 9 Hz, CHOH (anti)), 5.55 (s, 1H, CHOH (syn)), 7.36–
7.49 (m, 3H, ArH), 7.74–7.84 (m, 4H, ArH); 13C NMR (CDCl3,
300 MHz): d 24.5, 24.7, 25.9, 27.6, 27.8, 30.8, 42.5, 56.9, 57.3,
70.6, 74.7, 123.8, 124.4, 124.5, 125.5, 125.8, 125.9, 126, 126.1,
127.5, 127.6, 127.7, 127.8, 128.1, 132.5, 133, 133.1, 138.2, 138.8,
214.7, 215.4.
4.3.19. 2-[10-Hydroxy-10-(400-nitrophenyl)methyl]-4-tert-
butylcyclohexan-1-one 916c
Yield: 90%, enantiomeric excess: 92% of major diastereomer
determined by HPLC (Diacel Chiralpak OD-H; hexane/i-PrOH
92:8; flow rate 0.5 mL/min; k = 280 nm; tR (major) = 21.76 min, tR
(minor) = 24.70 min; 1H NMR (mixture of isomers) (CDCl3,
300 MHz): d 0.78, 0.81, 0.82 (3s, 9H, CH3), 1.40–1.67 (m, 4H, CH
and CH2), 2.09–2.15 (m, 1H, CH2), 2.40–2.52 (m, 2H, CH2), 2.65–
2.67 (m, 1H, CH), 3.14–3.15 (br s, 1H, OH), 4.95–4.98 (d, 0.3H,
J = 9 Hz, CHOH), 5.48 (s, 0.7H, CHOH), 7.47–7.55 (m, 2H, ArH),
8.19–8.25 (m, 2H, ArH); 13C NMR (mixture of isomers) (CDCl3,
300 MHz): d 26.7, 27.4, 27.5, 28.4, 28.5, 31.7, 32.4, 32.5, 41.8, 42,
46.4, 46.5, 55.8, 56, 70.1, 74.1, 123.4, 123.5, 126.5, 127.7, 147,
147.4, 148.4, 149.1.
4.3.15. 2-[10-Hydroxy-10-(400-nitrophenyl)methyl]-4-
methylcyclohexan-1-one 516b
Yield: 88%, enantiomeric excess: 95% of major diastereomer
determined by HPLC (Diacel Chiralpak AS-H; hexane/i-PrOH
70:30; flow rate 0.8 mL/min; k = 254 nm; tR (major) = 13.23 min,
tR (minor) = 18.45 min; 1H NMR (mixture of isomers) (CDCl3,
300 MHz): d 0.90–0.94 (m, 1H, CH3), 1.04–1.07 (m, 2H, CH3)
1.30–1.60 (m, 2H, CH2), 1.77–2.11 (m, 3H, CH and CH2), 2.32–
2.79 (m, 3H, CH2), 4.00 (br s, 1H, OH), 4.93 (d, 0.7H, J = 8.7 Hz,
CHOH), 5.47 (s, 0.3H, CHOH), 7.47–7.52 (m, 2H, ArH), 8.19–8.22
(m, 2H, ArH); 13C NMR (mixture of isomers) (CDCl3, 300 MHz): d

S. S. Chimni et al. / Tetrahedron: Asymmetry 19 (2008) 2276–2284
2283
4.3.20. 2-[10-Hydroxy-10-(200-nitrophenyl)methyl] cyclopent-1-
one 107a
(+ve), 123.4 (+ve), 126.7 (+ve), 127.3, 147.2, 149.3, 149.6, 215.4,
216.8.
Yield: 69%; anti/syn = 70:30; enantiomeric excess: 90% of anti
diastereomer determined by HPLC (Diacel Chiralpak AS-H; hex-
ane/i-PrOH 95:5; flow rate 1.0 mL/min, k = 225 nm; tR (syn, min-
or) = 22.75 min, tR (syn, major) = 36.83, tR (anti, major) =
28.22 min, tR (anti, minor) = 31.09 min; 1H NMR (CDCl3,
300 MHz): d 1.69–1.81 (m, 2H, CH2), 1.95–2.26 (m, 2H, CH2),
2.26–2.60 (m, 2H, CH2), 2.65–2.85 (m, 1H, CH), 4.50 (br s, 1H,
OH), 5.41–5.44 (d, 1H, J = 8.4 Hz, CHOH (anti)), 5.89–5.90 (d, 1H,
J = 3 Hz, CHOH (syn)), 7.38–7.57 (m, 1H, ArH), 7.59–7.72 (m, 1H,
ArH), 7.78–7.81 (m, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d 20.1,
20.4, 22.8, 26.5, 38.6, 54.7, 55.3, 66.4, 69.0, 123.9, 124.4, 127.9,
128.5, 128.6, 128.9, 133.1, 133.3, 138.6, 146.9, 219.1.
4.4. Procedure for regeneration of the catalyst 1o
After workup of reaction, the aqueous portion was separated
and neutralized with saturated solution of sodium carbonate. The
neutralized aqueous solution was extracted with dichloromethane
(3 ꢀ 10 mL), dried over anhydrous Na2SO4, and distilled to ob-
tained gummy material. It was titurated with equivalent amount
of 50% aqueous HBr and used for the aldol reaction.
Crystal suitable for X-ray analysis was obtained by recrystalliza-
tion from dichloromethane/methanol (95/5) at room temperature.
CCDC 688390 contains the supplementary cystallography data for
this compound.
4.3.21. 2-[10-Hydroxy-10-(300-nitrophenyl)methyl] cyclopent-1-
one 1116c
Acknowledgments
Yield: 78%; anti/syn = 52:48; enantiomeric excess: 80% of anti
diastereomer determined by HPLC (Diacel Chiralpak OD-H;
hexane/i-PrOH 93:7; flow rate 0.5 mL/min, k = 254 nm; tR
(syn, minor) = 35.02 min, tR (syn, major) = 42.60, tR (anti, ma-
jor) = 45.47 min, tR (anti, minor) = 53.98 min; 1H NMR (CDCl3,
300 MHz): d 1.50–1.89 (m, 2H, CH2), 1.90–2.58 (m, 4H, CH and
CH2), 2.89–3.12 (m, 1H, CH), 4.82–4.85 (d, 1H, J = 9 Hz, CHOH
(anti)), 5.42–5.43 (d, 1H, J = 2.7Hz, CHOH (syn)), 7.38–7.89 (m,
2H, ArH), 8.11–8.30 (m, 2H, ArH); 13C NMR (CDCl3, 300 MHz): d
18.3, 26.8, 33.2, 36.6, 38.5, 53.1, 69.7, 124.0, 128.4, 128.8, 133.1,
136.7, 148.7, 214.9.
We are grateful for the financial support from CSIR, India to SSC
(research Grant No. 01/1878/03/EMR-II) and JRF(NET) fellowship
to SS. The authors thank SAIF, Lucknow for providing Mass spectra
and National Facility, IIT Bombay, Mumbai (India) for X-ray
structure analysis. The support of Dr. B. S. Chadha is gratefully
acknowledged.
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4.3.22. 2-[10-Hydroxy-10-(400-nitrophenyl)methyl] cyclopent-1-
one 1216c
Yield: 74%; anti/syn = 56:44; enantiomeric excess: 73% of anti
diastereomer determined by HPLC (Diacel Chiralpak AD-H;
hexane/i-PrOH 95:5; flow rate 1.0 mL/min, k = 254 nm; tR (syn,
major) = 22.46 min, tR (syn, minor) = 29.77, tR (anti, minor) =
35.27 min, tR (anti, major) = 36.74 min; 1H NMR (CDCl3,
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4.3.23. 1-Hydroxy-1-(40-nitrophenyl)pentan-3-one 1316f
Yield 63%, enantiomeric excess: 50% determined by HPLC (Dia-
cel Chiralpak AS-H; hexane/i-PrOH 70:30; flow rate 0.5 mL/min,
k = 260 nm; tR (major) = 16.15 min, tR (minor) = 22.85; 1H NMR
(CDCl3, 300 MHz): d 1.07 (t, 3H, J = 7.2 Hz, CH3), 2.46 (q, 2H,
J = 7.2 Hz, CH2), 2.75–2.79 (m, 2H, CH2), 5.25–5.29 (m, 1H, CH),
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4.3.24. 1-Hydroxy-2-methyl-1-(40-nitrophenyl)pentan-3-one
1416g
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300 MHz): d 7.2 (+ve), 7.3 (+ve), 9.9 (+ve), 14.1 (+ve), 35.0 (ꢂve),
36.2 (ꢂve), 51.5 (+ve), 52.1 (+ve), 72.0 (+ve), 75.3 (+ve), 123.2
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