A new organocatalyst derived from abietic acid and 4-hydroxy-l-proline for direct asymmetric aldol reactions in aqueous media

Article abstract of DOI:10.1016/j.tetasy.2014.07.012

Enantioselective direct aldol reactions were carried out in aqueous media with a new organocatalyst that was derived from 4-hydroxy-l-proline and abietic acid via a simple and convenient synthetic protocol with a high overall yield (75%). The new organocatalyst was used for aldol reactions between substituted aromatic aldehydes and various ketones in the presence of several acid additives in aqueous media. The corresponding aldol products were obtained in high isolated yields (up to 99%) and with high anti-diastereoselectivities (up to 94%) and enantioselectivities (>99.9%). The catalyst loading can be efficiently reduced to only 1 mol %. The aldol reactions were found to be extremely fast which is very unusual in organocatalyzed reactions in water.

Full text of DOI:10.1016/j.tetasy.2014.07.012

Tetrahedron: Asymmetry 25 (2014) 1292–1297
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new organocatalyst derived from abietic acid and
4-hydroxy-L-proline for direct asymmetric aldol reactions
in aqueous media
Sudipto Bhowmick a, Sunita S. Kunte b, Kartick C. Bhowmick a,
⇑
a Division of Organic Synthesis, Department of Chemistry, Visva-Bharati University, Bolpur, West Bengal 731 235, India
b Division of Organic Chemistry, Analytical Section, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2014
Accepted 28 July 2014
Available online 11 September 2014
Enantioselective direct aldol reactions were carried out in aqueous media with a new organocatalyst that
was derived from 4-hydroxy-L-proline and abietic acid via a simple and convenient synthetic protocol
with a high overall yield (75%). The new organocatalyst was used for aldol reactions between substituted
aromatic aldehydes and various ketones in the presence of several acid additives in aqueous media. The
corresponding aldol products were obtained in high isolated yields (up to 99%) and with high anti-diaste-
reoselectivities (up to 94%) and enantioselectivities (>99.9%). The catalyst loading can be efficiently
reduced to only 1 mol %. The aldol reactions were found to be extremely fast which is very unusual in
organocatalyzed reactions in water.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
organocatalysts.7–9 It is believed that the creation of a hydrophobic
environment by the introduction of a suitable moiety into the cat-
Asymmetric organocatalysis is a metal free and environmentally
benign catalysis, which is currently a high profile field of research in
organic synthesis.1 It is evident that the magnitude of research on
asymmetric organocatalyzed aldol reaction is enormous compared
to the other types of carbonAcarbon bond forming reactions.1 Ini-
tial studies on the development of asymmetric organocatalyzed
aldol reactions were carried out by Hajos and Parrish in 1970s,
followed by Barbas, List, and Lerner in 2000.2 It was established that
alyst structure is a key factor for achieving excellent stereoselectiv-
ity.8d However, there is still a need to determine the ideal
hydrophobic backbone for 4-hydroxy-L-proline. Some terpene
structures have been found to be significant in this regard.8g,10
The requirement of a carbonyl functionality in the terpene moiety
for a better stereoselectivity was proposed by Tao et al.8g Herein
we have found that an organocatalyst even without a carbonyl
functionality in the terpene moiety is similarly effective. Organo-
L
-proline efficiently catalyzed intermolecular asymmetric aldol
reactions in organic solvents,2 but performed extremely poorly in
water.3 This changed entirely after the derivatization of
-proline
and 4-hydroxy-
-proline structures.4–9 Suitably modified deriva-
tives of -proline and 4-hydroxy-L-proline have been successfully
catalyst 1 with an abietic acid attachment on the 4-hydroxy-L-pro-
line was found to be successful with a lower catalyst loading in
aqueous media. Moreover, organocatalyst 1 could solve most of
the aforementioned disadvantages,4–9 since the synthesis of organ-
ocatalyst 1 is simple, the catalyst loading is low, and the catalysis is
extremely fast. Catalyst 1 was synthesized from two inexpensive
L
L
L
employed as catalysts for asymmetric aldol reactions in water.7–9
One modification was performed at the carboxylic acid functional-
naturally occurring components; 4-hydroxy-L-proline and abietic
ity of either
was aimed at the hydroxyl group of 4-hydroxy-
third modification was carried out simultaneously on both the
hydroxyl and carboxylic groups of 4-hydroxy-
-proline.9 However,
L
-proline or 4-hydroxy-
L
-proline;7 another modification
acid via a simple procedure with high overall yield and purity.
Herein we report that catalyst 1 with only 1 mol % loading pro-
vided aldol products with high isolated yields (up to 99%), high anti
diastereoselectivities (up to 94%), and optimum enantioselectivi-
ties (>99.9%) within 2–6 h of reaction in water. The unusually fast
rate of reaction in the presence of the new catalyst 1 with only
1 mol % loading is noteworthy in organocatalyzed asymmetric
transformations since such a fast catalytic activity with an extre-
mely low catalyst loading has been rarely observed in aqueous
media.7z
L
-proline8 while the
L
multistep and low yielding catalyst synthesis, slow catalysis in
water, and the need for high catalyst loading remained as some of
the fundamental limitations of the aforementioned derivatized
⇑
Corresponding author.
E-mail address: kartickc.bhowmick@visva-bharati.ac.in (K.C. Bhowmick).
http://dx.doi.org/10.1016/j.tetasy.2014.07.012
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

S. Bhowmick et al. / Tetrahedron: Asymmetry 25 (2014) 1292–1297
CH3
CH3
1293
CH3
CH3
L-4-hydroxy proline
H3C
H
H3C
CF3COOH, CF3SO3H
oxalyl chloride, DMF
rt, 3h
H
H
H
benzene, rt, 12h
95%
87%
OH
Cl
H3C
H3C
O
2
O
abietic acid
CH3
CH3
CH3
CH3
H3C
H
H3C
Et3N, EtOAc, rt
90%
H
O
H
H
O
O
O
H3C
H3C
O
O
OH
OH
N
N
H .HCl
1
H
3
Scheme 1. Preparation of the catalyst 1.
under neat conditions (entries 2 and 7, Table 1). It should be noted
that the addition of water (any volume) significantly enhanced the
enantioselectivity under similar reaction conditions (Table 1).
When the aldol reactions were performed under same reaction
conditions but without 4-nitrobenzoic acid as an additive, the
enantioselectivity decreased from 92% to only 56% (entries 4 and
1, respectively, Table 1). This indicates that water and the acid addi-
tive play a crucial role for the enhancement of the enantioselectiv-
ity in the aldol products. In the presence of both 1:3 and 1:10
volume ratios of aldehyde and ketone, we observed that 0.5 ml
was the optimum volume of water (entries 5 and 10, respectively,
Table 1). When the amount of water was increased or decreased
from 0.5 ml, the enantioselectivity as well as the diastereoselectiv-
ity decreased. The enantioselectivity was slightly better with a 1:10
2. Results and discussion
Catalyst 1 was prepared in only three steps and under very mild
and convenient reaction conditions. First abietic acid was converted
into its acid chloride 2 with oxalyl chloride, then subsequent
esterification between acid chloride 2 and 4-hydroxy-L-proline in
the presence of trifluoroacetic acid and trifluoromethane sulfonic
acid produced salt 3, which after triethylamine treatment
furnished the desired catalyst 1 in 75% overall yield (Scheme 1).
4-Hydroxy-L-proline derivative 1 was subsequently tested as an
organocatalyst for direct aldol reactions between 4-nitrobenzalde-
hyde and cyclohexanone. During the optimization study of the
aldol reaction between 4-nitrobenzaldehyde and cyclohexanone
with a ratio of 1:3 or 1:10, 87% enantioselectivity was obtained
Table 1
Effect of water and the aldehyde–ketone ratio
O
OH
O
O
1
catalyst (5 mol%)
H
+
4-nitrobenzoic acid (5 mol%), H2O, rt
NO2
NO2
4a
Entry
Aldehyde/ketone (mmol)
Water (ml)
Time (h)
Yielda (%)
anti/synb
eec (%)
1d
2
3
4
5
6
7
8
9
10
11
12e
13f
14
15e
16f
17g
1:3
1:3
1:3
1:3
1:3
1:3
1:10
1:10
1:10
1:10
1:10
1:3
1:3
1:5
1:5
1:5
0.1
—
0.01
0.1
0.5
1
2.5
2.5
2.5
3
4
4
9
7.5
5
6
5
15
14
6
17
16
48
95
93
94
99
92
96
92
94
96
96
98
93
86
95
94
98
—
70:30
93:7
91:9
92:8
95:5
93:7
89:11
93:7
92:8
93:7
94:6
91:9
93:7
95:5
93:7
96:4
—
56
87
90
92
97
96
87
93
99
99
98
96
97
97
96
98
—
—
0.01
0.1
0.5
1
0.5
0.5
0.5
0.5
0.5
0.5
1:5
a
b
c
d
e
f
Isolated yield after purification by column chromatography.
Diastereomer ratios (anti/syn) were determined by 1H NMR spectrum of the crude product mixture.
Determined by chiral HPLC analysis.
Reaction carried out in the absence of 4-nitrobenzoic acid.
In the presence of 0.5 mol % of catalyst 1.
In the presence of 1 mol % of catalyst 1.
g
In the absence of catalyst 1.

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S. Bhowmick et al. / Tetrahedron: Asymmetry 25 (2014) 1292–1297
Table 2
Effect of various acid additives
O
OH
O
O
catalyst 1 (1 mol%)
H
+
additive (5 mol%), H2O (0.5 ml), rt
NO2
NO2
4a
5 mmol
1 mmol
Entry
Additive (pKa)
Time (h)
Yielda (%)
anti/synb
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Benzoic acid (4.2)
Citric acid (3.14)
Tartaric acid (2.89)
Adipic acid (4.43)
Stearic acid (10.15)
2,4-Dinitrophenol (4.11)
Phthalic acid (2.98)
Picric acid (0.38)
Oleic acid (9.85)
TFA (0.23)
16
16
16
14
15
15
16
16
18
20
6
94
93
96
92
96
95
99
93
87
94
99
97
89
92:8
97:3
91:9
96:4
92:8
92:8
95:5
93:7
96:4
97:3
95:5
96:4
97:3
93
97
97
94
94
93
97
80
95
98
97
98
99
PTSA (ꢀ2.8)
Triflic (ꢀ12)
4
4
Methane sulfonic (ꢀ1.9)
a
b
c
Isolated yield after column chromatography.
Diastereomer ratios (anti/syn) were determined by 1H NMR spectrum of the crude product mixture.
Determined by chiral HPLC analysis of the anti isomer.
aldehyde–ketone ratio compared to 1:3 (entries 5 and 10, respec-
tively, Table 1). Although the 1:10 aldehyde–ketone ratio was found
to be better in affording the highest enantioselectivity (99%) in the
aldol products, we adopted a 1:5 ratio of aldehyde–ketone for sub-
sequent optimization studies to gain higher atom economy. It was
also observed that this lower aldehyde and ketone ratio (1:5) not
only kept the enantioselectivity (97%) almost unchanged, but also
provided an enhanced anti/syn diastereoselectivity (entry 14,
Table 1). During the catalyst loading optimization study, in the
presence of 0.5 ml of water it was found that as low as 1 mol % of
the catalyst was very effective and afforded as high as 98% enanti-
oselectivity with 1:5 aldehyde–ketone ratio (entry 16, Table 1). This
observation established the excellent catalytic activity of the newly
developed organocatalyst 1. An experiment without catalyst 1 was
also performed, where even after a 48 h reaction time, no product
formation was observed (entry 17, Table 1). Once the aldehyde–
ketone ratio (1:5), volume of water (0.5 ml), and catalyst loading
(1 mol %) were optimized, we next examined the effect of various
acid additives in the same aldol reaction. A variety of acid additives
with a wide range of pKa, starting from aromatic to aliphatic acids
such as benzoic acid, adipic acid, and so on afforded aldol adducts
with enantioselectivities ranging from 80% to 99% (Table 2).
All acid additives, except for picric acid, afforded excellent
enantioselectivities with a catalyst loading of only 1 mol %. The
reactions were comparatively slower in the presence of fatty acids
such as stearic and oleic acid, aromatic acids such as phthalic acid,
benzoic acid and 2,4-dinitrophenol, and aliphatic acids such as tar-
taric acid, citric acid, and adipic acid, but excellent enantioselectiv-
Table 3
Direct aldol reaction between various aromatic aldehydes and cyclohexanone with organocatalyst 1
O
OH
O
O
1 (1 mol%)
+
R1
R3
R1
R2
H
R3
CH3SO3H (5 mol%)
H2O (0.5 ml), rt
R2
(5 mmol)
(1 mmol)
4b-m, R1, R2 = -(CH2)4
-
, R , R2 = CH3
1
5a
5b, R1, R2 = -(CH2)3
-
Entry (aldol product)
R3CHO
Time (h)
Yielda (%)
anti/synb
eec (%)
1 4b
2 4c
3 4d
4 4e
5 4f
6 4g
7 4h
8 4i
9 4j
10 4k
11 4l
12 4m
13 5a
14 5b
o-Nitrobenzaldehyde
m-Nitrobenzaldehyde
o-Chlorobenzaldehyde
m-Chlorobenzaldehyde
p-Chlorobenzaldehyde
4-Methylbenzaldehyde
o-Fluorobenzaldehyde
m-Fluorobenzaldehyde
2-Naphthaldehyde
5
6
4
5
6
4
5
4
4
3
2
6
6
4
92
89
87
85
91
86
88
85
93
95
97
89
90
93
97:3
92:8
97:3
91:9
96:4
92:8
95:5
97:3
96:4
97:3
92:8
96:4
—
>99
96
>99
96
>99
95
>99
98
>99
95
>99
98
99
99.9
1-Naphthaldehyde
p-(Trifluoro)methyl-benzaldehyde
o-Methoxy benzaldehyde
p-Nitrobenzaldehyde
p-Nitrobenzaldehyde
97:3
a
b
c
Isolated yield after column chromatography.
Diastereomer ratios (anti/syn) were determined by 1H NMR spectrum of the crude product mixture.
Determined by chiral HPLC analysis of the anti isomer.

S. Bhowmick et al. / Tetrahedron: Asymmetry 25 (2014) 1292–1297
1295
ities were obtained (Table 2). Similar to other reports, sulfonic acid
3. Conclusion
additives with a lower pKa than carboxylic acid and phenol addi-
tives, furnished the aldol products with higher enantioselectivi-
ties.7y,9g,11 With catalyst 1, methanesulfonic acid afforded the
highest enantioselectivity (99%) and the reaction was completed
within 4 h (entry 13, Table 2). In these experiments, a non-linear
In conclusion, we have reported a new catalyst derived from
4-hydroxy- -proline that catalyzed a direct aldol reaction with
excellent diastereo- and enantioselectivities. The simple, short,
L
and inexpensive synthesis of organocatalyst 1 starting from readily
relationship (specifically
a non-monotonic relationship) was
available natural products, 4-hydroxy-L-proline and abietic acid,
observed between the pKa and obtained ees. The results of this
comprehensive acid additive study clearly indicated the require-
ment of a strong sulfonic acid additive for achieving best results
in terms of reactivity as well as selectivity with catalyst 1. The
requirement of a specific acid additive for a specific organocatalyst
makes it a useful and practical catalyst for the synthesis of stereo-
chemically pure aldol products. Unlike other organocatalysts
reported so far, catalyst 1 can perform with great reactivity in water
since most of the aldol reactions were completed in between 2 and
6 h at room temperature even with only 1 mol % of catalyst loading
in the presence of sulfonic acid additives.4–9 A single organocata-
lyst, similar to the present organocatalyst 1, has not been found
to solve simultaneously the major limitations such as multistep
and low-yielding catalyst synthesis, slow catalysis in water, high
catalyst loading, and poor to moderate selectivity in organocata-
lyzed asymmetric aldol reaction in water.4–9 Herein we have used
catalyst 1 with an abietic acid scaffold which has shown notewor-
thy results in asymmetric aldol reactions in water. Our results indi-
for optimum results is
a well established fact in the
literature.7d,j–l,q–t,w,y,z,8a,9f,g,11,12 Nevertheless, we were unsure as
to whether any unknown fundamental structural effect of the
methane sulfonic acid was responsible for the fastest reactivity
and highest selectivity in the present reaction, additional to known
facts such as reactivity enhancement through hydrogen bonding
and maintaining the pH of the reaction media.
Once all the parameters such as aldehyde–ketone ratio, water
volume, catalyst loading, and acid additive were optimized, we
next investigated the substituent effects of aromatic aldehydes in
aldol reactions in order to identify the scope and limitations of cat-
alyst 1, as shown in Table 3.
cate that the attachment of abietic acid on 4-hydroxy-L-proline
generates an ideal hydrophobic and as well as steric environment
in the catalyst structure, which can interact with the substrate mol-
ecules resulting in excellent diastereo- and enantioselectivities.
As can be seen from the results shown in Table 3, almost all of
the aromatic aldehyde substrates with either electron withdrawing
or electron donating substitution furnished the corresponding
aldol adducts with absolute enantiocontrol. It is also noteworthy
that all of the substrates showed very fast chemical reactivity,
which is very unusual in organocatalyzed aldol reactions in
water.4–9 We also checked the efficacy of catalyst 1 for aldol reac-
tions between various aliphatic ketones and p-nitrobenzaldehyde
under the same optimized reaction conditions. Two aliphatic
ketones such as acetone and cyclopentanone provided the corre-
sponding aldol adducts with excellent enantioselectivity and yields
within 4–6 h only (entries 13 and 14, Table 3).
We assume that, under the reaction conditions employed, a
hydrophobic region and a hydrophilic region formed in the pres-
ence of catalyst 1 (Fig. 1). A plausible transition state model is
shown in Figure 1 to explain the stereochemical outcome in the
present reaction. Theoretically it was established that free OH
groups of interfacial water molecules are responsible for the catal-
ysis through the activation of the aldehyde’s carbonyl group via the
formation of hydrogen bonds.13 A hypothesis regarding the similar
transition state has been discussed by Giacalone et al.14
4. Experimental
4.1. General
All reagents and starting materials were obtained from com-
mercial sources and used as received.
All dry solvents were purified using a solvent purification sys-
tem. Routine monitoring of the reaction was performed by TLC,
using precoated silica gel TLC plates obtained by E-Merck. All col-
umn chromatographic separations were carried out by using silica
gel (60–120 mesh). Petroleum ether used was of boiling range 60–
80 °C. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a 400 MHz Bruker spectrometer. Chemical shifts are
expressed in ppm downfield from TMS as internal standard. Infra-
red (IR) spectra were recorded on a FT-IR spectrometer (Shima-
dzu). Melting points were determined on a digital melting point
apparatus. Analytical high performance liquid chromatography
(HPLC) was carried out on (Shimadzu CLASS-VP V6.12 SP5) instru-
ment using Chiralpak AD-H (4.6 mm ꢁ 250 mm), Chiralpak Kroma-
sil 5-AmyCoat (4.6 mm ꢁ 250 mm), and Chiralcel OD-H
(4.6 mm ꢁ 250 mm) columns. Optical rotations were measured
on a Jasco Dip 360 digital polarimeter at k = 589 nm.
hydrophilic region
O
H2O
H2O
O
4.2. Synthesis of abietic acid chloride 2
HO
O
H3C
O
H
O
Oxalyl chloride (1.2 mmol, 0.1 ml) was added dropwise to a
solution of abietic acid (1 mmol, 302 mg) in dimethyl formamide
(0.004 mmol, 0.0003 ml) and dry benzene (0.72 ml) at room tem-
perature under a nitrogen atmosphere. The mixture was stirred
for 12 h and then concentrated in vacuo to afford abietic acid chlo-
ride 2 (304 mg, 95% yield).
N
H
H
H
O
H3C
H
CH3
R
CH3
hydrophobic region
4.3. Synthesis of (2S,4R)-4-((1R,4aR,4bR,10aR)-7-isopropyl-1,4a-
dimethyl-1,2,3,4,4a,4b,5,6,10,10a decahydrophenanthrene-1-
carbonyloxy)pyrrolidine-2-carboxylic acid 1
Figure 1. Possible transition state model for the formation of the major anti
enantiomer.
A 25 ml round bottomed flask was charged with CF3CO2H
(0.259 mL, 0.02 mmol) and placed in an ice/water bath. Powdered
This is the first time that such an unusually fast chemical reac-
tivity with excellent stereoselectivity has been observed in the
presence of only 1 mol % of organocatalyst in aqueous media.
trans-4-hydroxy-L-proline (70.7 mg, 0.54 mmol) was then added to
it in small portions with vigorous stirring to give a viscous solution

1296
S. Bhowmick et al. / Tetrahedron: Asymmetry 25 (2014) 1292–1297
(leaving some pieces of insoluble material). The reaction mixture
was stirred for 5 min and then the ice/water bath was removed.
To the resultant suspension, CF3SO3H (0.008 mL, 0.09 mmol) was
added. After 5 min of stirring, abietic acid chloride 2 (346.7 mg,
1.08 mmol) was added in one portion. The reaction flask was fitted
with a loose glass stopper, and the reaction mixture was stirred at
room temperature for 3 h. The reaction flask was then cooled in an
ice/water bath, and Et2O (5 mL) was added under vigorous stirring
over a period of 5 min. The resulting suspension was stirred at 0–
5 °C for 10 min and then filtered to obtain a brown salt 3 as a solid
excess of this sample was determined to be 96% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-
Hexane (15:85), Flow rate = 0.7 mL/min; k = 254 nm; tR (major) =
14.3 min, tR (minor) = 20 min.
4.4.4. (2S,10R)-2-[Hydroxy(2-chlorophenyl)methyl]cyclohexan-
1-one 4d
The spectroscopic NMR data were in agreement with the previ-
ously reported one.15c 25 = +21.5 (c 0.9, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-
Hexane (05:95), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
9.8 min, tR (minor) = 12.5 min.
product (211 mg, 87%). The crude brown salt
3 (211 mg,
0.47 mmol) was dissolved in the minimum volume of ethyl ace-
tate, and an equivalent amount of Et3N (0.06 ml, 0.47 mmol) was
added. The resulting white suspension was allowed to return to
room temperature after 5 min of stirring, and then filtered. The fil-
trate was evaporated to furnish 1 (179 mg, 90%) as a light yellow
4.4.5. (2S,10R)-2-[Hydroxy(3-chlorophenyl)methyl]cyclohexan-
1-one 4e
solid. Mp 68–69 °C; [
a]
20 = +10 (c 1.0, CHCl3); IR (film, cmꢀ1):
The spectroscopic NMR data were in agreement with the previ-
D
3593, 2925, 2302, 1722, 1396, 1236, 1114, 883; 1H NMR
(400 MHz, CDCl3) d 10.16 (s, 1H) 5.32 (s, 1H), 4.67 (s, 1H), 3.82–
3.9 (m, 1H), 2.9–2.96 (m, 2H) 2.24–2.37 (m, 7H) 1.84 (m, 3H)
1.68 (m, 2H) 1.25–1.30 (m, 12H) 0.84–1.03 (m, 7H); 13C NMR
(101 MHz, CDCl3) 8.5, 16.2, 18.3, 19.7, 21.7, 23.9, 24.3, 25.0, 25.1,
30.0, 32.8, 33.3, 36.4, 36.8, 37.7, 44.7, 45.9, 47.3, 50.6, 124.0,
126.8, 134.4, 145.6, 177.8, 182.0; ESI-MS (m/z): calcd for
ously reported one.15c 25 = +16.4 (c 1.1, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be 96% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-
Hexane (05:95), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
33.4 min, tR (minor) = 36.6 min.
4.4.6. (2S,10R)-2-[Hydroxy(4-chlorophenyl)methyl]cyclohexan-
1-one 4f
C25H37NO4 [MꢀH]: 414.2643; found: 414.2642.
The spectroscopic NMR data were in agreement with the previ-
4.4. General procedure for the enantioselective direct aldol reaction
ously reported one.15c 25 = +25.2 (c 0.1, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (15:85), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
9.6 min, tR (minor) = 12.9 min.
To a mixture of catalyst 1 (0.01 mmol) and additive (0.05 mmol)
in water (0.5 mL), ketone (5.0 mmol) followed by aromatic alde-
hydes (1.0 mmol) were added. The resulting mixture was stirred at
room temperatureto afford an emulsion. The asymmetric aldol reac-
tions were found to occur in emulsions where the catalyst molecules
were distributed in the water–oil interface. The reactions were mon-
itored by TLC. After the disappearance of the starting aldehyde, the
reaction mixture was quenched with 10 mL of saturated NaHCO3
solution, extracted with EtOAc (3 ꢁ 10 mL), and the organic layer
was treated with brine (15 mL), dried over Na2SO4, and concentrated
under vacuum. Purification of the crude products by column chro-
matography afforded the corresponding pure aldol products. The
ee of the products were determined by chiral HPLC analysis. The spe-
cific rotations were compared with the literature data.7c,15
4.4.7. (2S,10R)-2-[Hydroxy(4-mehylphenyl)methyl]cyclohexan-
1-one 4g
The spectroscopic NMR data were in agreement with the previ-
ously reported one.15c 25 = +13.1 (c 0.2, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be 95% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (3:97), Flow rate: 1 ml/min; k = 254 nm; tR (major) = 12.6 min,
tR (minor) = 17.2 min.
4.4.8. (2S,10R)-2-[Hydroxy(2-fluorophenyl)methyl]cyclohexan-
1-one 4h
4.4.1. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-
one 4a
The spectroscopic NMR data were in agreement with the previ-
ously reported one.14 25 = +22 (c 1, CHCl3). The enantiomeric
[a]
D
The spectroscopic NMR data were in agreement with the previ-
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (05:95), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
12.2 min, tR (minor) = 16.3 min.
ously reported one.15c 25 = +6.5 (c 0.1, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralpak Kromasil 5-CelluCoat, hexanes/iPrOH 95:5),
Flow rate = 0.7 mL/min; k = 254 nm; tR (major) = 23.5 min, tR
(minor) = 33.1 min.
4.4.9. (2S,10R)-2-[Hydroxy(3-fluorophenyl)methyl]cyclohexan-
1-one 4i
4.4.2. (2S,10R)-2-[Hydroxy(2-nitrophenyl)methyl]cyclohexan-1-
one 4b
The spectroscopic NMR data were in agreement with the previ-
ously reported one.7i 25 = +16.4 (c 1, CHCl3). The enantiomeric
[a]
D
The spectroscopic NMR data were in agreement with the previ-
excess of this sample was determined to be 98% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (05:95), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
15.1 min, tR (minor) = 20.9 min.
ously reported one.15c 25 = +25.3 (c 0.1, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (10:90), Flow rate = 0.7 mL/min; k = 254 nm; tR (major) =
15.9 min, tR (minor) = 18.8 min.
4.4.10. (2S,10R)-2-[Hydroxy(naphthalen-2-yl)methyl]cyclohexan-
1-one 4j
4.4.3. (2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclohexan-1-
one 4c
The spectroscopic NMR data were in agreement with the previ-
ously reported one.16 25 = +7.4 (c 0.1, CHCl3). The enantiomeric
[a]
D
The spectroscopic NMR data were in agreement with the previ-
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hexane
ously reported one.16
[
a]
D
25 = +29.3 (c 0.1, CHCl3). The enantiomeric

S. Bhowmick et al. / Tetrahedron: Asymmetry 25 (2014) 1292–1297
1297
3. Mase, N.; Barbas, C. F., III Org. Biomol. Chem. 2010, 8, 4043–4050.
(10:90), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) = 18.6 min,
tR (minor) = 23.8 min.
4. For recent discussions on proline and proline-derived organocatalysts, see the
reviews; (a) List, B.; Yamamoto, H. Synlett 2011, 461–512; (b) Butler, R. N.;
Coyne, A. G. Chem. Rev. 2010, 110, 6302–6337.
5. See the recent reviews (a) Bhowmick, S.; Bhowmick, K. C. Tetrahedron:
Asymmetry 2011, 22, 1945–1979; (b) Hernández, J. G.; Juaristi, E. Chem.
Commun. 2012, 5396–5409; (c) Raj, M.; Singh, V. K. Chem. Commun. 2009,
6687–6703; (d) Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23,
1431–1465; (e) Mlynarski, J.; Bas, S. Chem. Soc. Rev. 2014, 43, 577–587; (f) Bisai,
V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541–4580.
4.4.11. (2S,10R)-2-[Hydroxy(naphthalen-1-yl)methyl]cyclohexan-
1-one 4k
The spectroscopic NMR data were in agreement with the previ-
ously reported one.16 25 = +9.2 (c 1, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be 95% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (3:97), Flow rate: 1 ml/min; k = 254 nm; tR (major) = 34.2 min,
tR (minor) = 37.6 min.
6. See the very recent review on organocatalysis for CAC bond forming reactions:
Scheffler, U.; Mahrwald, R. Chem. Eur. J. 2013, 19, 14346–14396.
7. (a) He, T.; Li, K.; Wu, M.-Y.; Wu, M.-B.; Wang, N.; Pu, L.; Yu, X.-Q. Tetrahedron
2013, 69, 5136–5143; (b) Chimni, S. S.; Mahajan, D. Tetrahedron: Asymmetry
2006, 17, 2108–2119; (c) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett.
2006, 8, 4417–4420; (d) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G.
Org. Lett. 2007, 9, 1247–1250; (e) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007,
9, 2593–2595; (f) Huang, W.-P.; Chen, J.-R.; Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J.
Chem. 2007, 85, 208–213; (g) Gryko, D.; Saletra, W. J. Org. Biomol. Chem. 2007, 5,
2148–2153; (h) Wang, C.; Jiang, Y.; Zhang, X.-X.; Huang, Y.; Li, B.-G.; Zhang, G.-
L. Tetrahedron Lett. 2007, 48, 4281–4285; (i) Zu, L.; Xie, H.; Li, H.; Wang, J.;
Wang, W. Org. Lett. 2008, 10, 1211–1214; (j) Almaßsi, D.; Alonso, D. A.; Balaguer,
A.-N.; Nájera, C. Adv. Synth. Catal. 2009, 351, 1123–1131; (k) Wang, B.; Chen, G.-
H.; Liu, L.-Y.; Chang, W.-X.; Li, J. Adv. Synth. Catal. 2009, 351, 2441–2448; (l)
Mase, N.; Noshiro, N.; Mokuya, A.; Takabe, K. Adv. Synth. Catal. 2009, 351, 2791–
2796; (m) Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem. Eur. J.
2010, 16, 3842–3848; (n) Qin, L.; Zhang, L.; Jin, Q.; Zhang, J.; Han, B.; Liu, M.
Angew. Chem. Int. Ed. 2013, 52, 7761–7765; (o) Bayat, S.; Tejo, B. A.; Salleh, A. B.;
Abdmalek, E.; Normi, Y. M.; Rahman, M. B. A. Chirality 2013, 25, 726–734; (p)
Kumar, T. P.; Vavle, N. C.; Patro, V.; Haribabu, K. Tetrahedron: Asymmetry 2014,
25, 457–461; (q) Pedrosa, R.; Andrés, J. M.; Manzano, R.; Román, D.; Téllez, S.
Org. Biomol. Chem. 2011, 9, 935–940; (r) Pearson, A. J.; Panda, S. Org. Lett. 2011,
13, 5548–5551; (s) Tang, G.; Gün, Ü.; Altenbach, H.-J. Tetrahedron 2012, 68,
10230–10235; (t) Paladhi, S.; Das, J.; Mishra, P. K.; Dash, J. Adv. Synth. Catal.
2013, 355, 274–280; (u) Aratake, S.; Itoh, T.; Okano, T.; Usui, T.; Shoji, M.;
Hayashi, Y. Chem. Commun. 2007, 2524–2526; (v) Bellomo, A.; Daniellou, R.;
Plusquellec, D. Green Chem. 2012, 14, 281–284; (w) Mase, N.; Nakai, Y.; Ohara,
N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128,
734–735; (x) Angelici, G.; Corrêa, R. J.; Garden, S. J.; Tomasini, C. Tetrahedron
Lett. 2009, 50, 814–817; (y) Bhowmick, S.; Kunte, S. S.; Bhowmick, K. C. RSC Adv.
2014, 4, 24311–24315; (z) Wang, B.; Liu, X. –w.; Liu, L. –y.; Chang, W. –x.; Li, J.
Eur. J. Org. Chem. 2010, 5951–5954.
8. (a) Zhao, Q.; Lam, Y.-h.; Kheirabadi, M.; Xu, C.; Houk, K. N.; Schafmeister, C. E. J.
Org. Chem. 2012, 77, 4784–4792; (b) Zhong, L.; Gao, Q.; Gao, J.; Xiao, J.; Li, C. J.
Catal. 2007, 250, 360–364; (c) Fu, Y.-Q.; An, Y.-J.; Liu, W.-M.; Li, Z.-C.; Zhang, G.;
Tao, J.-C. Catal. Lett. 2008, 124, 397–404; (d) Aratake, S.; Itoh, T.; Okano, T.;
Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem. Eur. J. 2007, 13, 10246–
10256; (e) Huerta, E.; Stals, P. J. M.; Meijer, E. W.; Palmans, A. R. A. Angew.
Chem. Int. Ed. 2013, 52, 2906–2910; (f) Hayashi, Y.; Sumiya, T.; Takahashi, J.;
Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45, 958–961; (g)
An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu, Z.-M.; Pi, A.-C.; Tao, J.-C. Tetrahedron:
Asymmetry 2010, 21, 688–694; (h) Zheng, C.; Wu, Y.; Wang, X.; Zhao, G. Adv.
Synth. Catal. 2008, 350, 2690–2694.
9. (a) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Noto, R. Adv. Synth. Catal.
2008, 350, 1397–1405; (b) Zhao, J.-F.; He, L.; Jiang, J.; Cun, L.-F.; Gong, L.-Z.
Tetrahedron Lett. 2008, 49, 3372–3375; (c) Monge-Marcet, A.; Cattoën, X.;
Alonso, D. A.; Najerá, C.; Man, M. W. C.; Pleixats, R. Green Chem. 2012, 14, 1601–
1610; (d) Kristensen, T. E.; Vestli, K.; Jakobsen, M. G.; Hansen, F. K.; Hansen, T. J.
Org. Chem. 2010, 75, 1620–1629; (e) Kochetkov, S. V.; Kucherenko, A. S.; Zlotin,
S. G. Eur. J. Org. Chem. 2011, 6128–6133; (f) Delaney, J. P.; Henderson, L. C. Adv.
Synth. Catal. 2012, 354, 197–204; (g) Tzeng, Z.-H.; Chen, H.-Y.; Reddy, R. J.;
Huang, C.-T.; Chen, K. Tetrahedron 2009, 65, 2879–2888.
4.4.12. (2S,10R)-2-[Hydroxy(4-trifluoromethylphenyl)methyl]
cyclohexan-1-one 4l
The spectroscopic NMR data were in agreement with the previ-
ously reported one.16 25 = +1.7 (c 0.1, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be >99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (20:80), Flow rate: 0.5 ml/min; k = 254 nm; tR (major) =
12.1 min, tR (minor) = 14.1 min.
4.4.13. (2S,10R)-2-[Hydroxy(2-methoxyphenyl)methyl] cyclohexan-
1-one 4m
The spectroscopic NMR data were in agreement with the previ-
ously reported one.8g
[a]
25 = ꢀ23.6 (c 1, EtOAc). The enantiomeric
D
excess of this sample was determined to be 98% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (05:95), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
17.7 min, tR (minor) = 24.1 min.
4.4.14. (4R)-4-Hydroxy-p-nitrophenylbutan-2-one 5a
The spectroscopic NMR data were in agreement with the previ-
ously reported one.7w 25 = +64.6 (c 0.5, CHCl3). The enantiomeric
[a]
D
excess of this sample was determined to be 99% by chiral HPLC
analysis Chiralcel OD-H (250 ꢁ 4.6 mm), Mobile phase: IPA/n-Hex-
ane (8.5:91.5), Flow rate: 0.7 ml/min; k = 254 nm; tR (major) =
38.7 min, tR (minor) = 45.1 min.
4.4.15. (2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclopentan-
1-one 5b
The spectroscopic NMR data were in agreement with the previ-
ously reported one.7w
[
a]
25 = ꢀ30.8 (c 0.58, CHCl3). The enantio-
D
meric excess of this sample was determined to be >99.9% by
chiral HPLC analysis Chiralpak Kromasil-5AmyCoat (254 ꢁ 4.6),
Mobile phase: IPA/Pet Ether (10:90), Flow rate: 1 ml/min;
k = 265 nm; tR (major) = 21.3 min.
Acknowledgments
10. Narayanaperumal, S.; Rivera, D. G.; Silva, R. C.; Paixao, M. W. ChemCatChem
2013, 5, 2756–2773.
11. Zhao, H.; Meng, W.; Yang, Z.; Tian, T.; Sheng, Z.; Li, H.; Song, X.; Zhang, Y.; Yang,
S.; Li, B. Chin. J. Chem. 2014, 32, 417–428.
12. Eymur, S.; Akceylan, E.; Sahin, O.; Uyanik, A.; Yilmaz, M. Tetrahedron 2014, 70,
1–7.
13. Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492–5502.
14. Giacalone, F.; Gruttadauria, M.; Meo, P. Lo.; Riela, S.; Noto, R. Adv. Synth. Catal.
2008, 350, 2747–2760.
The authors are grateful to the DST, Govt. of India for the finan-
cial assistance [Grant No. SR/FT/CS-013/2009] and S.B. thanks the
UGC, Govt. of India for the award of a research fellowship.
References
15. (a) Kanemitsu, T.; Umehara, A.; Miyazaki, M.; Nagata, K.; Itoh, T. Eur. J. Org.
Chem. 2011, 5, 993–997; (b) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–
4652; (c) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Meo, P. L.; Riela, S.;
Noto, R. Eur. J. Org. Chem. 2007, 28, 4688–4698; (d) Demircan, E.; Eymur, S.;
Demir, A. S. Tetrahedron: Asymmetry 2014, 25, 443–448; (e) Thorat, P. B.;
Goswami, S. V.; Khade, B. C.; Bhusare, S. R. Tetrahedron Lett. 2012, 53, 6083–
6086.
1. (a) GrÖger, H.; Wilken, J.; Berkessel, A. Organic Synthesis Highlights V; Wiley-
VCH: Weinheim, 2003. pp 178–186; (b) Berkessel, A.; GrÖger, H. Asymmetric
Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weiheim, 2005; (c) List, B. Chem. Rev. 2007, 107,
5413–5883; (d)Modern Methods in Stereoselective Aldol Reactions; Mahrwald, R.,
Ed.; Wiley-VCH: Weinheim, 2013.
2. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621; (b) Notz, W.;
List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387; (c) List, B.; Lerner, R. A.; Barbas,
C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396.
16. Wu, C.; Fu, X.; Ma, X.; Li, S. Tetrahedron: Asymmetry 2010, 21, 2465–2470.