A novel trifunctional organocatalyst for the asymmetric aldol reaction: A facile enantioselective synthesis of β-hydroxyketones

Article abstract of DOI:10.1016/j.tetasy.2011.05.001

A new l-prolinamide trifunctional catalyst has been developed for the enantioselective aldol reaction of various aromatic and aliphatic aldehydes with acetone. This method provides high yields of β-hydroxyketones (up to 90%) with good enantioselectivity (up to 92%) at a low catalyst loading (10 mol %).

Full text of DOI:10.1016/j.tetasy.2011.05.001

Tetrahedron: Asymmetry 22 (2011) 881–886
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel trifunctional organocatalyst for the asymmetric aldol reaction:
a facile enantioselective synthesis of b-hydroxyketones
⇑
B. V. Subba Reddy , K. Bhavani, A. Raju, J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new L-prolinamide trifunctional catalyst has been developed for the enantioselective aldol reaction of
Received 7 April 2011
Accepted 6 May 2011
Available online 21 June 2011
various aromatic and aliphatic aldehydes with acetone. This method provides high yields of b-hydroxy-
ketones (up to 90%) with good enantioselectivity (up to 92%) at a low catalyst loading (10 mol %).
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
H
HN
The stereoselective aldol reaction is one of the most powerful
synthetic methods for the synthesis of b-hydroxy carbonyl com-
pounds,1 which are subunits of many natural products; the reac-
tion has also been utilized in the synthesis of polyoxygenated
OH
O
I
N
CHO
NO2
O
+
compounds. Since the first report of L-proline catalysed enantiose-
10 mol %
lective C–C bond formation2 via an intermolecular aldol reaction
by List et al.,3 there has been great progress in proline catalysed di-
rect aldol reactions. A number of catalysts have been reported with
NO2
DMF, -40 oC
2
1
3a
Scheme 1. Asymmetric aldol reaction of 2-nitrobenzaldehyde with acetone cata-
lysed by prolinamide I.
a modified acidic moiety of L-proline. The asymmetric direct aldol
reaction4 does not require a preformed enolate and thus makes it
more atom economical. The major proline derived organocatalysts
are mainly 4-substituted L-proline, proline derived N-sulfonyl car-
and III were prepared from N-Boc-L-proline and the corresponding
boxamide small peptides, different types of prolinamides and other
chiral amino acids.5–7 However, the catalytic systems, which give
high enantioselectivity with broad substrate scope at a low catalyst
loading and with reasonable timings are still in demand.
Many of the aforementioned proline derivatives or other organ-
ocatalysts8 are bifuntional, and contain one or more additional ste-
reogenic centres that are often found to catalyse direct aldol
reactions leading to products with high enantioselectivities. Thus,
the catalytic potentials of simple prolinamide derivatives remain
unexplored.
amino compounds, respectively, according to the synthetic route
shown in Scheme 2.
Deprotection of the Boc group using 5 M HCl in THF/H2O (3:1)
afforded the prolinamides I, II and III in good yields (Fig. 1).
We envisaged that L-prolinamide I may induce enantioselectiv-
ity due to rigidity within the catalyst I. The quinoline ring of
the catalyst could be anticipated to interfere in the transition
state of the aldol reaction in such a way that it controls the
enantioselectivity.
Accordingly, the catalytic performance of prolinamide catalysts
was examined in a direct aldol reaction between o-nitrobenzalde-
hyde and acetone in a variety of solvents without any additives at
different temperatures. The results are summarized in Table 1. Of
2. Results and discussion
these,
L-prolinamide I gave the Aldol product with good ee. Ini-
Herein, we report a facile enantioselective direct aldol reaction
of acetone with various aromatic aldehydes using a novel trifunc-
tional L-prolinamide catalyst I (Scheme 1).
tially, the aldol reaction was performed at room temperature using
L
-prolinamide I under neat conditions. Interestingly, 10 mol % of
-prolinamide I showed very high reactivity in the aldol reaction
L
The catalyst I was prepared from 8-aminoquinoline and N-Boc-
-proline (Scheme 1). Similarly, other prolinamide derivatives II
of 2-nitrobenzaldehyde with acetone (Scheme 1). The reaction pro-
ceeded smoothly at room temperature under solvent free condi-
tions and was complete within 2 h. Although the corresponding
aldol 3a was obtained in 90% yield, the enantiomeric excess was
low (65%).
L
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.001

882
B. V. Subba Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 881–886
O
O
EDCI, HOBT
+
CH2Cl2, 0oC-rt
N
N
OH
N
HN
5h, 90%
Boc
NH2
Boc
N
5M HCl
THF:H2O, rt
4h, 85%
O
N
H
HN
N
Scheme 2. Synthesis of (S)-N-(quinolin-8-yl)pyrrolidine-2-carboxamide I.
bulk of the catalyst, which may play an important role in the
O
O
stereoselectivity. Moreover, when the loading of the catalyst was
decreased from 10 to 5 mol %, there was no change in the enantio-
meric excess but the reaction took 11 h to afford similar results
(Table 2).
N
S
N
H
N
H
HN
HN
N
I
II
Table 2
HO
O
Efficacy of various L-proline derivatives in the synthesis of 3a
O
O
Me
Entry
Catalyst (mol %)
Time (h)
Yielda (%)
eeb (%)
N
H
HN NH
N
H
OH
N
H
OH
a
b
c
d
e
f
I (10 mol %)
I (5 mol %)
6.0
11.0
4.0
90
88
93
70
75
64
74
92
92
92
69
65
63
69
S
O
III
V
IV
L-proline derivatives.
I (20 mol %)
II (10 mol %)
III (10 mol %)
IV (10 mol %)
V (10 mol %)
O
8.5
13.0
14.0
12.0
Figure 1. Various
g
a
Yield refers to pure products after chromatography.
Ee % was calculated by chiral HPLC.
Table 1
Effect of solvent in the synthesis of 3a using L-prolinamide
b
Entry
Solvent
Time (h)
Yielda (%)
eeb,c (%)
Next, we examined the scope and generality of this process with
a
b
c
d
e
f
DMF
THF
MeCN
Water
Acetone
Chloroform
Toluene
6.0
12.0
8.5
14.0
8.5
90
55
70
50
60
75
50
92
90
69
45
65
89
55
various aldehydes under optimized conditions; the results are pre-
sented in Table 3.
The best results were obtained with ortho-nitrobenzaldehyde
(Table 3, entry a). Similarly other nitro substituted benzaldehydes
also produced the corresponding products in good yields with good
enantioselectivities (Table 3, entries b, c and g). The halo and cyano
substituted benzaldehydes were also effective for this conversion
(Table 3, entries d, e and h). In the case of naphthaldehyde, both
the yield and enantioselectivity were moderate (Table 3, entry f).
Aliphatic aldehydes were not so effective, therefore, the yield and
enantioselectivity were low with aliphatic aldehydes (Table 3, en-
tries i and j). In the case of p-methoxybenzaldehyde, the enantiose-
lectivity and yield were very low (Table 3, entry l). This may be due
to the electron donating ability of the methoxyl group, which may
increase the electron density at the carbonyl group.
14.0
12.0
g
a
b
c
Yield refers to pure products after chromatography.
Ee % was calculated by chiral HPLC.
Reactions were performed at ꢀ40 °C.
The reaction conditions were further optimized with
L
-prolina-
mide I to increase the ee of 3a. The results, as shown in Table 1,
reveal that the aldol reaction was successful in many organic sol-
vents, but good yields and high enantioseletivity were observed
in DMF. Although a slight difference in enantioselectivity was ob-
served in THF and CHCl3, the reaction required longer reaction
times. However, the enantiomeric excess decreased further when
water was used as a solvent. By further optimizing the reaction
conditions, the enantioselectivity was increased to 78% at 0 °C.
When decreasing the reaction temperature to ꢀ40 °C, product 3a
was obtained with 92% ee. It was found that the enantioselectivity
was dependent on the reaction temperature. The best enantiose-
The stereochemistry of the Aldol products was assigned by
comparing the spectral data with the data reported in literature.5
On the basis of experimental results, the high stereocontrol was
observed when L-prolinamide (I) was used which can be rational-
ized by the above presumed transition state9 and also the steric
crowding plays an important role in stereoselectivity (Fig. 2).
3. Conclusion
lectivity was obtained in the direct aldol reaction by L-prolinamide
I, when the temperature was low (ꢀ40 °C), though the reaction
In conclusion, we have developed some novel trifunctional
L-prolinamide catalysts for a direct enantioselective aldol reaction.
was sluggish (6.5 h). This result is presumably due to the steric

B. V. Subba Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 881–886
883
Table 3
Organocatalytic asymmetric Aldol reaction using 8-ammoquinoline derived L-prolineamide (I)
Entry
Aldehyde
Product (3)a
OH
Time (h)
6.5
Yieldb (%)
eec (%)
92
Configurationd
CHO
NO2
O
a
90
R
R
R
NO2
CHO
CHO
OH
OH
O2N
O
O
O2N
b
c
6.0
7.0
85
87
77
80
O2N
O2N
CHO
O
OH
d
e
f
8.0
8.0
7.5
5.5
85
85
75
90
73
65
62
70
R
R
R
R
Cl
Cl
Cl
Cl
CHO
O
OH
Cl
Cl
O
OH
CHO
CHO
O
OH
g
NO2
O2N
NC
NO2
OH
O2N
NC
CHO
O
h
i
7.5
9.0
9.5
85
55
45
72
52
51
R
R
R
CHO
O
OH
CHO
CHO
O
OH
OH
j
O
k
l
7.0
75
60
63
50
R
R
CHO
O
OH
10
MeO
MeO
a
b
c
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
The ee value of the product was determined by chiral HPLC analysis.
d
The absolute configuration was assigned by comparison with known compounds.
Of these catalysts,
catalyst for the aldol reaction of acetone with various aldehydes.
L
-prolinamide I proved to be the most efficient
good yields (up to 90%) with high enantioselectivity (up to 92%
ee) under mild reaction conditions. Further exploration of the
This catalyst produces the corresponding b-hydroxy ketones in
L-prolinamide I is currently in progress in our group.

884
B. V. Subba Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 881–886
less oil (2.0 g). ½a D25
ꢂ
¼ þ19:1 (c 1.0, CHCl3); IR (neat):
m 3320.3,
O
2963.5, 1681.5, 1528.4, 1486.4, 1381.3, 1324.8, 1769.4, 877.6,
H
828.2, 793.4, 758.4, 590.5 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
N
N
1.56–1.832 (m, 2H), 2.02–2.28 (m, 2H), 3.05–3.13 (m, 2H), 3.94
(q, J = 5.4 Hz, 1H), 7.31–7.55 (m, 3H), 8.08 (dd, J = 1.7, 8.3 Hz, 1H),
8.75–8.83 (m, 2H), 11.54 (br s, 1H); 13C NMR (75 MHz, CDCl3): d
26.2, 30.9, 47.4, 61.8, 116.3, 121.3, 127.2, 127.9, 134.4, 136.0,
139.1, 148.5, 174.1; ESI-MS: (m/z) 242 (M+H)+; HRMS calcd for
N
H
O
H3C
H
Figure 2. A proposed transition state for the aldol reaction.
C
14H16N3O 242.1293, found 242.1294.
4.4. General procedure for the enantioselective aldol reaction
The catalyst, -prolinamide 1 (0.1 mmol) was stirred in 5 mL of
4. Experimental
L
4.1. General procedure
acetone/DMF (9:1) for 30 min at ꢀ40 °C. To this solution, the cor-
responding aldehyde (1 mmol) was added and the resulting mix-
ture was stirred for appropriate time (see Table 3). The reaction
mixture was quenched with a saturated aqueous ammonium chlo-
ride solution and then extracted with ethyl acetate (3 ꢁ 10 mL).
The organic layer was washed with water and dried over Na2SO4.
After evaporation of the solvent under reduced pressure, the crude
product was purified by column chromatography over silica gel
using ethyl acetate/hexane (2:8) as eluent to afford the pure the al-
dol product. The enantiomeric excess was determined by chiral
HPLC with Daicel Chiralpak AD-H.
The spectroscopic data of 1H and 13C NMR were recorded in
CDCl3 solvent on a Bruker AV-300 MHz spectrometer and chemical
shifts are reported in ppm. Mass spectra were recorded on VG
micromass-7070H (70 eV). The optical rotations were recorded
on Perkin Elmer (model 343) digital polarimeter. HPLC analysis
was performed on a Schimadzu liquid chromatography using a chi-
ral pak AD-H column with isopropyl alcohol and hexane as eluents.
All starting materials were prepared according to the literature
procedures. All products were purified by column chromatography
using silica gel (Merck 60–120 mesh), eluent petroleum ether–
EtOAc.
4.4.1. (R)-4-Hydroxy-4-(2-nitrophenyl)butan-2-one10 3a
Colourless oil, ½a D25
ꢂ
¼ ꢀ107 (c 1.2, CHCl3); IR (neat):
m 3416,
4.2. Preparation of (S)-tert-butyl 2-(quinolin-8-
2934, 1719, 1512, 1376 cmꢀ1 1H NMR (300 MHz, CDCl3): d 2.22
;
ylcarbamoyl)pyrrolidine-1-carboxylate 4
(s, 3H), 2.59–2.74 (m, 1H), 2.98–3.12 (m, 1H), 5.58–5.67 (m, 1H),
7.36–7.45 (m, 1H), 7.59–7.68 (m, 1H), 7.85–7.97 (m, 2H); 13C
NMR (75 MHz, CDCl3): d 30.3, 51.1, 65.5, 125.0, 128.0, 128.2,
133.9, 138.1, 147.2, 207.9; ESI-MS: (m/z) 210 (M+1)+; enantiomeric
excess: 92%, determined by HPLC analysis using chiral pak AD-H
250 ꢁ 4.6 mm, 5u, column (isopropanol/hexanes 1:9), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 8.33 min, minor iso-
mer tR 12.41 min.
To a stirred solution of N-t-butyloxycarbonyl-L-proline 3 (2 g,
7.9 mmol) in dry dichloromethane (10 mL), was added HOBT
(1.2 g, 25 mmol). The mixture was allowed to stir for 15 min and
then cooled to 0 °C and then EDCI (2.3 g, 56 mmol) was added.
After 20 min, a solution of 8-aminoquinoline (2.6 g, 69 mmol) in
dichloromethane (10 mL) was added to the above reaction mix-
ture. The resulting mixture was stirred for 5 h at room tempera-
ture. After completion as monitored by TLC, the reaction was
quenched with water and extracted with dichloromethane
(3 ꢁ 50 mL). The combined organic layers were washed with satu-
rated brine solution (10 mL), followed by drying over Na2SO4 and
evaporating in vacuo. The crude product was purified by column
chromatography (EtOAc/hexane, 40:60) to give the pure amide 4
4.4.2. (R)-4-Hydroxy-4-(3-nitrophenyl)butan-2-one10 3b
Colourless oil, ½a D25
ꢂ
¼ þ58:2 (c 0.45, CHCl3); IR (neat):
m 3414,
2931, 1715, 1519, 1370 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 2.21
(s, 3H), 2.82–2.89 (m, 2H), 3.60–3.77 (m, 1H), 5.23 (t, J = 6.7 Hz,
1H), 7.46–7.55 (m, 1H), 7.65–7.77 (m, 1H), 8.08–8.22 (m, 2H);
13C NMR (75 MHz, CDCl3): d 30.2, 51.0, 65.6, 124.2, 128.0, 128.1,
133.6, 138.4, 146.9, 208.6; ESI-MS: (m/z) 232 (M+Na)+; enantio-
meric excess: 77%, determined by HPLC analysis using chiral pak
AD 250 ꢁ 4.6 mm, 5u, column (ethanol/hexanes 1:9), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 21.03 min, minor
isomer tR 31.31 min.
as a colourless solid (3.2 g, 85% yield). ½a D25
¼ ꢀ304:6 (c 1.0, CHCl3);
ꢂ
IR (KBr):
m 3288.1, 2975.1, 2925.2, 2864.3, 1678.4, 1527.6, 1418.8,
1250.5, 1161.8, 827.7, 796.5, 760.0, 574.3, 538.9 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 1.34 (s, 9H), 1.89–2.09 (m, 2H), 2.23–2.39
(m, 2H), 3.40–3.77 (m, 2H), 4.34–4.62 (m, 1H), 7.35–7.59 (m,
3H), 8.06–8.19 (m, 1H), 8.71–8.86 (m, 2H), 10.29 (br s, 1H); 13C
NMR (50 MHz, CDCl3): d 23.8, 28.1, 29.5, 46.9, 62.3, 80.3, 116.2,
121.5, 127.0, 127.7, 133.9, 135.9, 136.1, 138.4, 148.1, 154.3,
171.2; ESI-MS: (m/z) 364 (M+Na)+.
4.4.3. (R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one10 3c
Colourless oil, ½a D25
ꢂ
¼ þ53:2 (c 0.42, CHCl3); IR (neat):
m 3419,
2930, 1716, 1514, 1480, 1370 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d
2.23 (s, 3H), 2.84–2.89 (m, 2H), 3.68 (d, J = 2.4 Hz, 1H), 5.27–5.29
(m, 1H), 7.54–8.20 (m, 4H); 13C NMR (75 MHz, CDCl3): d 30.7,
51.4, 68.8, 123.7, 126.2, 147.1, 149.7, 208.2; ESI-MS: (m/z) 210
(M+1)+; enantiomeric excess: 80%, determined by HPLC analysis
using Diacel AD-H 250 ꢁ 4.6 mm, 5u, column (isopropanol/hex-
anes 1:9), UV, 210 nm, flow rate 1.0 ml/min, major isomer tR
21.03 min, minor isomer tR 31.31 min.
4.3. Preparation of (S)-N-(quinolin-8-yl)pyrrolidine-2-
carboxamide I
At first, Boc-amide 4 (2.0 g) was dissolved in a mixture of 5 M
HCl/THF (1:6) (5 mL:30 mL) at 0 °C and the stirring was continued
for 4 h at room temperature. After completion as monitored by
TLC, the reaction was quenched with saturated NaHCO3 solution
and extracted with EtOAc (3 ꢁ 50 mL). The organic layers were
dried over Na2SO4. After removal of the solvent, the crude residue
was purified through column chromatography on silica gel (ethyl
4.4.4. (R)-4-(2,4-Dichlorophenyl)-4-hydroxybutan-2-one10 3d
Colourless oil, ½a D25
ꢂ
¼ þ39:5 (c 0.44, CHCl3); IR (neat):
m 3414,
2932, 1718, 1517, 1373, 1167, 689 cmꢀ1
;
1H NMR (300 MHz,
acetate/hexane 1:1 as eluent) to afford
L
-prolinamide 1 as a colour-
CDCl3): d 2.20 (s, 3H), 2.49–2.62 (m, 1H), 3.50–3.63 (m, 1H), 5.38

B. V. Subba Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 881–886
885
(d, J = 9.4 Hz, 1H), 7.23–7.35 (m, 2H), 7.53–7.60 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 30.4, 50.2, 65.9, 127.3, 127.6, 128.9, 131.3,
133.4, 138.7, 208.9; ESI-MS: (m/z) 255 (M+Na)+; enantiomeric ex-
cess: 73%, determined by HPLC analysis using Diacel
AD-H, 250 ꢁ 4.6 mm, 5u, column (ethanol/hexanes 1:9), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 8.99 min, minor iso-
mer tR 10.67 min.
1H), 2.51–2.62 (m, 2H), 3.73–3.87 (m, 1H); enantiomeric excess:
51%.
4.4.11. (R)-Hydroxy-4-phenylbutan-2-one10 3k
Colourless oil, ½a D25
ꢂ
¼ þ65 (c 0.4, CHCl3); IR (neat):
m 3413, 2934,
1718, 1452, 890 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 2.17 (s, 3H),
2.75–2.80 (m, 1H), 2.98–3.11 (m, 1H), 5.04–5.15 (m, 1H), 7.17–
7.33 (m, 5H); EI-MS: (m/z) 164 (M+1)+; enantiomeric excess:
63%, determined by HPLC analysis using chiral pak AD-H
250 ꢁ 4.6 mm, 5u, column (isopropanol/hexanes 1:9), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 8.1 min, minor iso-
mer tR 8.9 min.
4.4.5. (R)-4-(4-Chlorophenyl)-4-hydroxybutan-2-one10 3e
Colourless oil, ½a D25
ꢂ
¼ þ33:2 (c 0.7, CHCl3); IR (neat):
m 3418,
2934, 1713, 1489, 1369, 1077, 538 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d 2.21 (s, 3H), 2.70–2.82 (m, 2H), 3.44 (d, J = 3.2 Hz, 1H),
5.11–5.15 (m, 1H), 7.29–7.35 (m, 4H); 13C NMR (75 MHz, CDCl3):
d 30.6, 51.4, 68.7, 127.0, 128.1, 133.3, 141.1, 207.8; ESI-MS: (m/z)
221 (M+Na)+; enantiomeric excess: 55%, determined by HPLC anal-
ysis using chiral pak AD-H, 250 ꢁ 4.6 mm, 5u, column (isopropa-
nol/hexanes 1:9), UV, 210 nm, flow rate 1.0 ml/min, major isomer
tR 8.77 min, minor isomer tR 9.37 min.
4.4.12. (4R)-Hydroxy-4(4-methoxyphenyl)-butan-2-one10 3l
Colourless oil, ½a D25
ꢂ
¼ þ42 (c 0.45, CHCl3); IR (neat):
m 3422,
2917, 1728, 1455, 1108, 1075 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
2.21 (s, 3H), 2.75–2.86 (m, 2H), 3.82 (s, 3H), 5.15 (dd, J = 9.0,
3.3 Hz 1H), 6.91 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H); enantio-
meric excess: 50%, determined by HPLC analysis using chiral pak
AD-H 250 ꢁ 4.6 mm, 5u, column (isopropanol/hexanes 1:9), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 9.2 min, minor iso-
mer tR 10.3 min.
4.4.6. (R)-4-Hydroxy-4-(naphthalene-1-yl)butan-2-one10 3f
Colourless oil, ½a D25
ꢂ
¼ þ72 (c 0.2, CHCl3); IR (neat):
m 3421, 3050,
2923, 1687, 1614 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 2.22 (s, 3H),
3.00–3.20 (m, 1H), 3.46 (d, J = 3.3 Hz, 1H), 5.87–5.96 (m, 1H), 7.47–
7.54 (m, 3H), 7.71 (d, J = 10.3 Hz, 1H), 7.81 (d, J = 11.4 Hz, 1H),
7.88–8.00 (m, 2H); 13C NMR (75 MHz, CDCl3): d 29.7, 50.1, 65.4,
121.4, 121.8, 124.2, 125.0, 126.7, 127.7, 128.7, 129.0, 131.0,
136.7, 207.6; ESI-MS: (m/z) 237 (M+Na)+; enantiomeric excess:
62%, determined by HPLC analysis using chiral pak AD-H,
250 ꢁ 4.6 mm, 5u, column (isopropanol/hexanes 1:9), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 14.01 min, minor
isomer tR 17.19 min.
Acknowledgement
K.B. and A.R. thank CSIR, New Delhi for the award of
fellowships.
References
1. Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2,
pp 229–275.
2. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany,
2004; Vols. 1 and 2,.
4.4.7. (R)-4-Hydroxy-4-(2,4-dinitrophenyl)butan-2-one 3g
Colourless oil, ½a D25
ꢂ
¼ ꢀ21:8 (c 0.4, CHCl3); IR (neat):
m 3399,
2923, 1697, 1607, 1535, 1344, 1218, 1085 cmꢀ1
;
1H NMR
3. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396.
4. (a) List, B. Acc. Chem. Res. 2004, 37, 548–557; (b) Saito, S.; Yamamoto, H. Acc.
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Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1983–1986; (g) Hartikka,
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Aprile, C.; Meo, P. L.; D’Anna, F.; Noto, R. Adv. Synth. Catal. 2006, 348, 82–92; (d)
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(300 MHz, CDCl3): d 2.25 (s, 3H), 2.62–2.80 (m, 1H), 3.01–3.18
(m, 1H), 4.0 (br s, 1H), 5.71–5.84 (m, 1H), 8.12–8.27 (m, 1H),
8.45–8.57 (m, 1H), 8.77–8.88 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 30.3, 50.6, 65.3, 119.9, 127.6, 130.2, 145.2, 146.7, 146.9, 207.8;
ESI-MS: (m/z) 277 (M+Na)+; enantiomeric excess: 70%, determined
by HPLC analysis using chiral pak AD-H, 250 ꢁ 4.6 mm, 5u, column
(isopropanol/hexanes 1:9), UV, 210 nm, flow rate 1.0 ml/min, ma-
jor isomer tR 22.36 min, minor isomer tR 27.44 min.
4.4.8. 3-((R)-1-Hydroxy-3-oxobutyl)benzonitrile 3h
Colourless oil; ½a D25
ꢂ
¼ þ21 (c 0.6, CHCl3); IR (neat):
m 3455,
2923, 2230, 1712, 1527, 1460, 1364, 1162 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 2.20 (s, 3H), 2.78–2.82 (m, 2H), 5.12–5.18
(m, 1H), 7.41–7.48 (m, 1H), 7.53–7.68 (m, 3H); 13C NMR
(75 MHz, CDCl3): d 30.6, 51.4, 68.5, 112.2, 118.8, 129.1, 130.0,
131.0, 144.3, 208.4; ESI-MS: (m/z) 212 (M+Na)+; enantiomeric ex-
cess: 72%, determined by HPLC analysis using chiral pak AD-H,
250 ꢁ 4.6 mm, 5u, column (isopropanol/hexanes 1.2:8.8), UV,
210 nm, flow rate 1.0 ml/min, major isomer tR 21.80 min, minor
isomer tR 24.56 min.
7. (a) Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 739–748; (b) Tang, Z.; Jiang,
F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A.
4.4.9. (R)-4-Hydroxy-5-methylhexan-2-one11 3i
´
2004, 101, 5755–5760; (c) Gryko, D.; Lipin Ski, R. Adv. Synth. Catal. 2005, 347,
Colourless oil, ½a D25
ꢂ
¼ þ53:2 (c 0.4, CHCl3); IR (neat):
m 3410,
1948–1952; (d) Guo, H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A. Q.; Jiang, Y.-Z. Chem.
Commun. 2005, 1450–1452; (e) Chen, J.-R.; Lu, H. H.; Li, X.-Y.; Cheng, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543–4545.
2930, 1718, 1353, 703 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 0.80–
1.0 (m, 6H), 1.60–1.77 (m, 1H), 2.21 (s, 3H), 2.53–2.57 (m, 2H),
2.93 (br s, 1H), 3.77–3.87 (m, 1H); enantiomeric excess: 52%.
8. (a) Guo, H.-M.; Cun, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem. Commun. 2005, 1450–
1452; (b) Martin, H. J.; List, B. Synlett 2003, 1901–1902; (c) Kofoed, J.; Nielsen,
J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445–2447; (d) Krattiger, P.;
Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101–1103;
(e) Ikishima, H.; Sekiguchi, Y.; Ichikawa, Y.; Kotsuki, H. Tetrahedron 2006, 62,
311–316.
4.4.10. (R)-4-Cyclohexyl-4-hydroxybutan-2-one11 3j
Colourless oil, ½a D25
ꢂ
¼ ꢀ33:4 (c 0.7, CHCl3); IR (neat):
m 3419,
2931, 1715, 1450, 1364, 1165 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
9. (a) Chimni, S. S.; Singh, S.; Mahajan, D. Tetrahedron: Asymmetry 2008, 19, 2276–
2284; (b) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K.
0.90–1.23 (m, 6H), 1.63–1.80 (m, 5H), 2.20 (s, 3H), 2.23–2.41 (m,

886
B. V. Subba Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 881–886
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10. Zhou, Y.; Shan, Z. Tetrahedron: Asymmetry 2006, 17, 1671–1677.
11. Jiang, M.; Zhu, S.-F.; Yang, Y.; Gong, L.-Z.; Zhou, X.-G.; Zhou, O.-L. Tetrahedron:
Asymmetry 2006, 17, 384–387.
Chem. Soc. 2005, 127, 11294–11302; (d) Davies, S. G.; Russell, A. J.; Sheppard, R.
L.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3190–3200; (e)
Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Chem. Commun. 2005,
3802–3804.