Direct enantioselective aldol reactions catalyzed by calix[4]arene-based l-proline derivatives in the water

Article abstract of DOI:10.1016/j.tet.2014.05.034

Two novel p-tert-butylcalix[4]arene-based chiral organocatalysts derived from l-proline have been developed to catalyze direct aldol reactions between cyclohexanone and aromatic aldehydes in water. Under the optimal conditions, high yields (up to 95%), en

Full text of DOI:10.1016/j.tet.2014.05.034

Tetrahedron 70 (2014) 4471e4477
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Direct enantioselective aldol reactions catalyzed by calix[4]arene-
based -proline derivatives in the water
L
*
Serkan Eymur, Ezgi Akceylan, Ozlem Sahin, Arzu Uyanik, Mustafa Yilmaz
Selcuk University, Department of Chemistry, 42031 Konya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel p-tert-butylcalix[4]arene-based chiral organocatalysts derived from L-proline have been de-
Received 24 January 2014
Received in revised form 22 April 2014
Accepted 8 May 2014
veloped to catalyze direct aldol reactions between cyclohexanone and aromatic aldehydes in water.
Under the optimal conditions, high yields (up to 95%), enantioselectivities (up to 90%), and moderate
diastereoselectivities (up to 65:35) were obtained. Considering the catalytic inefficiency of sole proline
for the aldol reaction in water, these results clearly display the enormous effect of the hydrophobic part
of calix[4]arene of compound A.
Available online 16 May 2014
Keywords:
Calix[4]arene
Organocatalysis
Aldol
Ó 2014 Elsevier Ltd. All rights reserved.
Water
1. Introduction
alkyl chains and an acid to perform a direct aldol reaction in the
presence of water.8 They postulated that a small organic catalyst
The aldol reaction has been one of the most efficient methods for
CeC bond forming reactions, creating -hydroxy ketones, which are
with suitable large hydrophobic substituents should assemble with
hydrophobic reactants in water and diminish contacts between
bulk water and the reaction transition states. Since then, it has
generally been thought that good efficiencies in water may be ac-
complished within ‘hydrophobic activation’, linking proline de-
rivatives to suitable hydrophobic moieties.9
b
involved in the structure of many biologically important compounds
that also pertain to pharmaceutical fields.1 In particular, asymmetric
aldol reactions have gained great attention in the past few decades.2
Following the pioneering work of the proline-catalyzed asymmetric
direct aldol reaction by List et al. in the early 2000s,3 organo-
catalyzed asymmetric aldol reactions were professed to be a pow-
erful tool in asymmetric organic synthesis. Since the inspiration of
these studies originated from nature’s CeC bond forming reactions
utilizing class I aldolase enzymes,4 the development of enantiose-
lective transformations using water as a reaction medium has
attracted great interest in the scientific community because of the its
low cost, safety, and environmentally benign nature.5 Unfortunately,
while proline catalyzes direct aldol reactions with high enantiose-
lectivity in polar organic solvents, almost racemic products were
obtained in the presence of water or a buffer solution because water
interferes with the organocatalysts and disturbs hydrogen bonds as
well as other polar interactions.6 In this context, much attention has
already been given to the problem in order to find new methodol-
ogies including new types of organocatalysts for improving the
enantioselectivities of the aldol reaction products in water.5,7
In 2006, Barbas and Hayashi independently reported the com-
bined use of proline-derived chiral catalyst bearing hydrophobic
Calixarenes, with their unique three-dimensional surface and
conformationally rigid structure, are one of the best-known mac-
rocyclic organic host compounds of phenolic units linked by
methylene or groups at the 2,6-positions. The capability of being
modified at either the upper and/or lower rims of the molecular
skeleton has made this class of macrocyclic compounds in-
creasingly attractive for the scientists involved in the field of su-
pramolecular chemistry.10 Considering the intramolecular
hydrophobic cavities of calixarenes, we note that it is crucial for
catalysis that a hydrophobic platform is required, which may allow
reaction to proceed in the presence of water. Once the possibilities
of modification for these macromolecules make them suitable for
asymmetric reactions, it is not unexpected that calixarene-based
organocatalysts have been developed for a direct aldol reaction in
aqueous solutions.11 However, to the best of our knowledge a direct
aldol reaction catalyzed by calixarene bearing proline moiety in the
presence of a large amount of water has not been yet described.
We believe that the development of proline derivatives with
large hydrophobic moieties capable of catalyzing enantioselective
aldol reactions using water as a solvent is still attracting great in-
terest. Taking into account our longstanding research into
* Corresponding author. Tel.: þ90 332 2233873; fax: þ90 332 2410520; e-mail
address: myilmaz42@yahoo.com (M. Yilmaz).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.034

4472
S. Eymur et al. / Tetrahedron 70 (2014) 4471e4477
calixarenes,10e,12 herein, we thought it of interest to design a novel
When the reaction proceeded in organic solvents, the anti-iso-
mer was obtained with moderate diastereoselectivity and low
conversion. Common organic solvents, such as chloroform, DMSO,
acetonitrile, DMF, and ethanol were not suitable for both catalysts A
and B; only low enantiomeric excess was determined within 24 h
when these solvents were used (Table 1, entries 1e9). When the
reaction medium was changed from organic solvents to water, we
were pleased to notice an increased conversion and enantiose-
lectivity of corresponding aldol product (Table 1, entries 10 and 11).
When the reaction was performed in water with 20 mol % catalyst A,
the formation of aldol product was observed in 90% conversion and
46% ee (Table 1, entry 10). Encouraged by the results, we next
evaluated the effect of catalyst loading on reactivity and selectivity.
We found that the relative amount of catalyst could be reduced to
10 mol % without significant loss in reactivity and selectivity (Table
1, entry 12). Remarkably, catalyst loadings as low as 5 mol % could
also be utilized without significant loss in enantiocontrol (Table 1,
entry 13).
class of organocatalysts by coupling
represented in Fig. 1.
L-proline with calix[4]arenes as
We envisioned that the special hydrophobic cavities of such
derivatives would facilitate the aldol reaction in water. The role
played by the hydrophobic effect of calix[4]arene on the conversion
and stereoselectivity of the reaction is studied here and the results
discussed.
O
Large apolar group
(Calixarene moiety)
N
NH
H
: Calix[4]arene moiety
We then investigated the effect of different amounts of water by
using catalyst A. We selected catalyst A due to the faster reaction
times and higher isolated yields compared to those of catalyst B
with similar levels of selectivity. As seen in Table 2, when 440 equiv
Fig. 1. Schematic representation of organocatalysts examined in this study.
2. Results and discussions
of water (1000
2, entry 1). Moreover, using 220 equiv of water (500
m
L) was used, a high conversion was observed (Table
2.1. Catalyst preparation
mL) gave better
results both in terms of yield and stereoselectivity (Table 2, entry 2).
It should be noted that a small amount of water does not interrupt
the reaction at all. The reaction proceeds smoothly even in the
presence of 18 equiv of water to provide nearly the same enantio-
selectivity (Table 2, entry 5).
In order to confirm the role of the hydrophobic calixarene
platform of A and B, monomeric analog (catalyst C) of A was also
prepared according to routine methods (Scheme 2). A key control
Catalysts A and B were readily prepared according to routine
methods (Scheme 1).
First, tert-butylcalix[4]arene 1 was reacted with 3-bromopropyl
phthalimide in the presence of K2CO3 to give bis(3-
phthalimidopropoxy)calix[4]arene 2.13 The phthalimido groups
were removed with hydrazine hydrate in EtOH to result in bis(3-
aminopropoxy)calix[4]arene 3.13 The Boc-protected
L-proline was
reacted with bis(3-aminopropoxy)calix[4]arene by N,N0-dicyclo-
hexylcarbodiimide (DCC) coupling method to result in compound 4
in 73% yield. Then direct deprotection of the Boc group by tri-
fluoroacetic acid (TFA) in dichloromethane quantitatively resulted
in the catalyst A in 70% yield. Catalyst B was synthesized using an
acid chloride method. The reaction of acid chloride 614 with N-(2-
reaction was carried out because more simple L-proline derivatives
are known to be good catalysts for the asymmetric aldol reactions.
In control experiment, low conversion and diastereoselectivity
were observed by using catalyst C (Table 1, entry 14).
These observations all clearly demonstrate the importance of
the hydrophobic part of the calix[4]arene skeletons in compounds
A and B for the reaction to proceed in the presence of water. The
aminoethyl)-N0-(tert-butoxycarbonyl)- -prolinamide15 results in
L
the corresponding diamide derivative of calix[4]arene 7 in 75%
yield. The formation of compound 7 was confirmed by the ap-
pearance of the characteristic amide band at about 1666 cmꢀ1 in
the IR spectra. Catalyst B was finally obtained by TFA treatment
with 71% yield from compound 7. The chemical structures of these
highest enantiomeric excess was obtained by using 250 mL of water
(Table 2, entry 3), and thus all further reactions were performed
using this volume of water. Moreover, it was also found that good
results were obtained when neat reaction conditions were
employed (Table 2, entry 7).
organocatalysts A and B were completely characterized by 1H, 13
C
In the literature, it has been shown that additives, bases, or acids
are sometimes needed to improve the rate and enantioselectivity of
the reaction by promoting the enamine formation.17 We were then
inspired to perform the enantioselective aldol reaction in the
presence of additives to find out the optimal working conditions
(Table 3). First benzoic acid (PhCOOH) was used as an additive
because it is commonly used in aldol reactions. The reaction time
was notably shortened from 24 h to 16 h when 20 mol % PhCOOH
was employed (Table 3, entry 1). Acetic acid also furnished a com-
parable enantioselectivity of 75% under the same reaction condi-
tions. The additive trifluoroacetic acid and PTSA were also used, but
all provided low to poor conversions, as shown in entries 3 and 4 of
Table 2. From the results it is clear that 20 mol % chloroacetic acid
was found to be the best additive in terms of conversion as well as
selectivity (Table 3, entry 6). The different amounts of chloroacetic
acid were also tested, but there was no improvement of enantio-
selectivity as shown in entries 7 and 8 of Table 3.
NMR, and IR analyses. The conformational characteristics of calix[4]
arenes were conveniently estimated by way of the splitting pattern
of the ArCH2Ar methylene protons in the 1H and 13C NMR spectra.10
1H and 13C NMR data showed that newly synthesized chiral p-tert-
butylcalix[4]arene derivatives A and B are in a cone conformation.16
A typical AB pattern was observed for the methylene bridge
ArCH2Ar protons at
d
d
3.33 and 4.23 ppm (J¼12.9 Hz) for A, and
3.29e3.63 and 4.53 ppm (J¼12.9 Hz) for B in 1H NMR. The high
field doublets at
d 3.33 ppm for A and d 3.29e3.63 ppm for B were
assigned to the equatorial protons of the methylene groups,
whereas the low field signals at d 4.23 ppm for A and 4.53 ppm for B
were assigned to the axial protons in the 1H NMR.
2.2. Optimization of aldol condensations
In an initial experiment, we studied the aldol reaction using
cyclohexanone and p-nitrobenzaldehyde in the presence of orga-
nocatalysts (A, B) and water. Organic solvents were also employed
as the reaction medium. The reaction conditions parameters, such
as catalyst loading, amount of solvent, and temperature were firstly
evaluated.
2.3. Substrate scope
With these optimal conditions in hand, we next sought to in-
vestigate the scope of this asymmetric catalytic aldol reaction. All

S. Eymur et al. / Tetrahedron 70 (2014) 4471e4477
4473
A
H2N
N-GP
O
NH2
N-PG
O
OH
OH
OH O
HO
OH
OH
OH
O
OH
(ii)
(i)
2
3
1
N
N
HN
HN
NH
NH
Boc
Boc
O
O
O
O
O
HN
NH
3
OH
DCC
CH2Cl2
TFA
CH2Cl2
N
Boc
OH
OH
O
O
OH
OH
O
O
4 (73%)
Catalyst A (70%)
O
O
O
O
B
Cl
Cl
HO
OH
OH
OH
O
OH
OH HO
OH
O
O
OH
OH
O
(c)
(a), (b)
5
6
1
HN
HN
NH
NH
N
N
Boc
Boc
O
O
O
O
O
HN
NH
NH2
TFA
CH2Cl2
N
H
6
N
NH
NH
HN
HN
Boc
O
O
O
O
O
OH
OH
O
OH O
O
OH
7
(75%)
Catalyst B (%71)
Scheme 1. Synthesis of catalysts A and B. Reagents and conditions: (i) N-(3-bromopropyl)phthalimide, K2CO3, CH3CN; (ii) NH2NH2, ethanol (a) Methylbromoacetate, K2CO3, acetone,
(b) NaOH, ethanol, (c) thionyl chloride, DCM. PG (protecting group): phthalimide.

4474
S. Eymur et al. / Tetrahedron 70 (2014) 4471e4477
Table 1
Optimization of reaction conditions for the direct enantioselective aldol reaction of cyclohexanone with p-nitrobenzaldehyde catalyzed by compound A or Ba
O
O
OH
O
Catalyst A or B
H
Solvent, r.t., 24h
O2N
NO2
Entry
Solvent
Catalyst: mol %
Conv.b (%)
anti/synb
eec (%)
1
2
3
4
5
6
7
8
CHCl3
CHCl3
DMSO
DMSO
CH3CN
CH3CN
DMF
DMF
EtOH
H2O
A: 20%
B: 20%
A: 20%
B: 20%
A: 20%
B: 20%
A: 20%
B: 20%
A: 20%
A: 20%
B: 20%
A: 10%
A: 5%
41
39
50
51
39
35
15
10
<15
90
60:40
56:44
64:36
60:40
56:44
58:42
52:48
53:47
60:40
65:35
58:42
67:33
54:46
56:42
8
6
13
10
12
9
n.d.
n.d.
n.d.
46
38
48
40
n.d.
9
10
11
12
13
14
H2O
H2O
H2O
H2O
70
93
36
<10
C: 10%
a
Reaction conditions: cyclohexanone (200
mL, 2.0 mmol), aldehyde (17.0 mg, 0.125 mmol), catalyst, and water (1.0 mL).
b
c
Determined by 1H NMR of crude mixture.
The ee value of anti-isomer was determined by chiral HPLC analysis in comparison with authentic racemic material.
Table 2
The effect of the amount of water present on compound A catalyzed aldol reactiona
Table 3
The effect of different additives on the aldol reaction catalyzed by compound Aa
Entry
Amount of water (
m
L)
Conv.b (%)
anti/synb
eec (%)
Entry
Additive: mol %
Conv.b (%)
anti/synb
eec (%)
1
3
4
5
6
7
1000 (440 equiv)
500 (220 equiv)
250 (110 equiv)
125 (55 equiv)
40 (18 equiv)
d
93
97
99
90
94
80
67:33
65:35
65:35
61:39
60:40
55:45
48
50
56
48
55
52
1
2
3
4
5
6
7
8
PhCOOH: 20
CH3COOH: 20
TFA: 20
95
91
<10
<10
90
95
94
95
65:35
58:42
54:46
52:48
56:44
64:36
60:40
61:39
77
76
22
n.d.
75
90
82
85
PTSA: 20
CCl3COOH: 20
ClCH2COOH: 20
ClCH2COOH: 30
ClCH2COOH: 10
a
Reaction conditions: cyclohexanone (200
0.125 mmol), catalyst (10 mol %), and water.
mL, 2.0 mmol), aldehyde (17.0 mg,
b
Determined by 1H NMR of crude mixture.
c
a
The ee value of anti-isomer was determined by chiral HPLC analysis in com-
Reaction conditions: cyclohexanone (200
m
L, 2.0 mmol), aldehyde (17.0 mg,
L).
parison with authentic racemic material.
0.125 mmol), catalyst (10 mol %), and water (250
m
b
Determined by 1H NMR of crude mixture.
The ee value of anti-isomer was determined by chiral HPLC analysis in com-
c
parison with authentic racemic material.
N
HN
HN
Boc
NH2
O
HN
O
Table 4
O
Aldol reaction of different aldehydes with cyclic ketones catalyzed by compound A
O
N
OH
TFA
CH2Cl2
O
Boc
O
OH
O
O
O
Catalyst A (10 %mol)
ClCH2COOH(20 %mol)
R
DCC, CH2Cl2
R
H
Water (0.250 mL), r.t., 24 h
2 mmol
0.125 mmol
9
8
10a-i
8
Yielda (%)
anti/synb
eec (%)
9 (77%)
Entry
Aldehyde (R)
Catalyst C (75%)
1
2
3
4
5
6
7
8
9
4-NO2Ph
4-ClPh
4-FPh
4-BrPh
3-ClPh
3-NO2Ph
2-ClPh
2-NO2Ph
4-OMePh
95
78
83
84
90
80
90
78
40
65:35
60:40
64:36
64:36
62:38
63:37
60:40
64:36
56:44
90
72
77
80
74
82
76
83
50
Scheme 2. Synthesis of catalyst C. Reagents and conditions: (i) N-(3-bromopropyl)
phthalimide, K2CO3, CH3CN; (ii) NH2NH2, ethanol.
reactions were performed at room temperature in the presence of
10 mol % of A for 16 h. Aromatic aldehydes with different sub-
stitution patterns on the phenyl ring, including electron-
withdrawing groups and electron-releasing groups, were tested
as aldol acceptors. We chose nitro and halogen substituents as
representative electron-withdrawing groups and a methoxy sub-
stituent as an electron-donating group on the benzene ring. As
shown in Table 4, aromatic aldehydes with electron-withdrawing
a
Isolated yield after flash column chromatography on silica gel.
b
c
Determined by 1H NMR of crude mixture.
The ee value of anti-isomer was determined by chiral HPLC analysis in com-
parison with authentic racemic material.

S. Eymur et al. / Tetrahedron 70 (2014) 4471e4477
4475
groups are good acceptors and give the desired products in good
yields with high enantioselectivity and moderate diaster-
eoselectivity (72e90% ee; Table 4, entries 1e9). p-Anisaldehyde
was poor substrate for the aldol reaction giving low yield (40%) and
low enantioselectivity (Table 4, entry 9). The highest selectivities
were observed with the 4-NO2-benzaldehyde.
All the aforementioned results lead us to propose a mechanism
based on general enamine catalysis for the reaction performed in
the presence of a large amount of water. As depicted in Fig. 2, we
propose that a hydrophobic region and a hydrophilic region can be
generated by the formation of hydrogen bonds between free OH
groups of interfacial water molecules and OH groups of the calix[4]
arene moiety, which enhance the activity of organic catalysis on
water. The transition state can be explained according to
a HoukeList model.18
(ppm) using solvent as an internal standard (CDCl3 at 77.0 ppm).
Column chromatography was conducted on silica gel 60 (mesh size
40e63 mm). TLC was carried out on aluminum sheets precoated
with silica gel 60F254 (Merck). Visualization was accomplished with
UV light and anisaldehyde followed by heating. The enantiomeric
excess (ee) of products was determined by chiral-phase HPLC
analysis.
4.2. Synthesis of compound A
Boc-L
-proline (1.05 g, 4.2 mmol) and N,N0-dicyclohex-
ylcarbodiimide (DCC) (1.2 g, 5.8 mmol) were dissolved in CH2Cl2
(20 mL) and cooled down to 0 ꢁC. After the solution was stirred for
30 min, a solution of bis(3-aminopropoxy)calix[4]arene13 (1.5 g,
1.96 mmol) in dichloromethane (100 mL) was added and the
mixture was stirred for 60 h at room temperature. Solvent was
removed under reduced pressure. The residue was dissolved in
CH2Cl2 (150 mL) and the organic layer extracted three times with
water. The combined organic phases were dried (anhydrous
MgSO4), the solvent was removed under reduced pressure. Com-
pound 4 was obtained in 73% yield; mp 104e105 ꢁC. IR: 1698 cmꢀ1
HN
Hydrophobic region
O
H
N
(C]O). 1H NMR (400 MHz, CDCl3) (ppm): 0.99 (s, 18H, tBu),1.26 (s,
d
H
O
18H, tBu), 1.41 (s, 18H, tBu), 1.5e2.28 (m, 12H, CH2CH2(proline),
OCH2CH2CH2), 3.32 (d, 4H, J¼13.5 Hz, ArCH2Ar), 3.45e3.69 (m, 8H,
CH2N, CH2NH), 4.01 (m, 4H, CH2O), 4.21 (m, 6H, ArCH2Ar, NCHCO),
6.8 (s, 4H, ArH), 7.03 (s, 4H, ArH). 13C NMR (100 MHz, CDCl3): 173.5
(NHCO), 153.4 (NCOO), 150.2, 149.4, 147.1, 141.6, 132.5, 127.5, 125.7,
125.1, 79.9, 74.0, 61.0, 60.1, 46.9, 34.0, 31.7, 31.0, 28.4, 24.4, and 23.5.
Anal. Calcd for: C70H100O10N4: C, 72.63; H, 8.71; N, 4.84%. Found: C,
72.67; H, 8.77; N, 4.88%.
O
H
O
O
O
H2O
H
O
H
O
H
H
O
Compound 4 (0.25 g, 0.26 mmol) was dissolved in a mixture of
TFA/CH2Cl2 (1:4) (20 mL), and stirred for 10 h at room temperature.
The mixture was basified with concentrated ammonia solution and
extracted with CH2Cl2 (3ꢂ15 mL). After the removal of the solvent
at reduced pressure, the residue was purified by recrystallization in
a mixture of hexane/ethyl acetate. Compound A was obtained in
70% yield; mp 139e141 ꢁC. IR: 1670 cmꢀ1 (C]Oamide). 1H NMR
Hydrophilic region
H
O
H
N
O
H
O
HN
t
t
(400 MHz, CDCl3):
d (ppm): 1.02 (s, 18H, Bu), 1.26 (s, 18H, Bu),
Fig. 2. Proposed structure of catalyst A in the presence of water.
1.5e2.28 (m, 12H, CH2CH2 (proline), OCH2CH2CH2), 2.83e2.96 (m,
4H, CH2NHCH), 3.33 (m, 4H, ArCH2Ar), 3.65e3.74 (m, 4H,
OCH2CH2CH2N), 3.93e4.07 (m, 4H, OCH2CH2CH2), 4.23 (m, 4H,
ArCH2Ar), 6.86 (s, 4H, ArH), 7.04 (s, 4H, ArH), 7.79 (s, 2H, ArOH), 8.17
(t, J¼6.2 Hz, 2H, NHCO). 13C NMR (100 MHz, CDCl3): 175.0 (NHCO),
150.0, 149.4, 148.3, 147.1, 141.8, 132.6, 127.6, 125.6, 125.2, 73.8, 60.4,
47.2, 47.0, 38.1, 36.2, 34.0, 33.8, 31.6, 30.9, 26.0, 22.5, and 14.16. Anal.
Calcd for: C60H84O6N4: C, 75.28; H, 8.84; N, 5.85%. Found: C, 75.30;
H, 8.85; N, 5.88%.
3. Conclusion
In summary, we designed and synthesized two novel p-tert-
butylcalix[4]arene-based chiral organocatalysts derived from
L-proline. We have investigated that compound A can catalyze
enantioselective aldol reactions directly in the presence of water.
Under the optimal conditions, high yields (up to 95%), enantiose-
lectivities (up to 90%), and moderate diastereoselectivities (up to
65:35) were obtained. The reaction is proposed to work via the
HoukeList model. Considering the catalytic inefficiency of sole
proline for the aldol reaction in water, these results clearly dem-
onstrate the enormous effect of the hydrophobic part of calix[4]
arene of compound A on the reactivity and selectivity in water,
without the need to use low temperatures.
4.3. Synthesis of compound B
25,27-Bis(chlorocarbonylmethoxy)-26,28-hydroxycalix[4]arene
(6)14 (6.2 g, 5.44 mmol) was dissolved in CH2Cl2 (25 mL). The ad-
dition of pyridine (1 mL) and the solution of amine (N-(2-amino-
ethyl)-N0-(tert-butoxycarbonyl)- -prolinamide)15 (7.96 g, 31 mmol)
L
in CH2Cl2 (10 mL) was made sequentially and added dropwise over
about 1 h with continuous stirring at room temperature. The re-
action mixture was then stirred for 3 h at room temperature, after
which most of the solvent was distilled off in vacuo. The residue
was diluted with water (200 mL) and neutralized by 0.1 M HCl. The
solid material was then filtered and washed with 2 M HCl, NaHCO3,
and distilled water, sequentially. Compound 7 was obtained in 75%
yield; mp 142e144 ꢁC. IR: 1666 cmꢀ1 (C]O). 1H NMR (400 MHz,
4. Experimental section
4.1. General
NMR spectra were recorded on a Varian 400 MHz spectrometer.
1H NMR spectra are reported in parts per million (ppm) using
solvent as an internal standard (CHCl3 at 7.26 ppm). Data are re-
ported as s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br m¼broad multiplet; coupling constant(s) in hertz (Hz); in-
tegration. Proton-decoupled 13C NMR spectra were recorded on
a 100 MHz spectrometer and are reported in parts per million
CDCl3):
d d (ppm): 1.06 (s, 18H,
(ppm): 1H NMR (CDCl3, 400 MHz)
C(CH3)3),1.24 (s,18H, C(CH3)3),1.43 (s,18H, OC(CH3)3),1.55e2.17 (br
m, 8H, CH2CH2(proline)), 3.30e3.53 (br m, 16H, NCH2, ArCH2Ar),
3.87e4.02 (m, 2H, CH), 4.14 (d, 4H, J¼13 Hz, ArCH2Ar), 4.60 (s, 4H,

4476
S. Eymur et al. / Tetrahedron 70 (2014) 4471e4477
OCH2), 6.85 (s, 2H, OH), 6.95 (s, 4H, ArH), 7.26 (s, 4H, ArH),
7.95e8.08 (m, 2H, NH), 8.98e9.10 (m, 2H, NH). 13C NMR (100 MHz,
CDCl3): 172.1, 169.0, 154.3, 149.2, 148.7, 143.0, 132.3, 127.0, 126.1,
125.7, 79.9, 74.6, 61.0, 59.7, 46.8, 39.7, 38.8, 33.9, 31.4, 30.8, 28.3,
24.4. Anal. Calcd for: C71H100O12N6: C, 69.35; H, 8.20; N, 6.83%.
Found: C, 69.32; H, 8.24; N, 6.80%.
Compound 7 (0.25 g, 0.20 mmol) was dissolved in a mixture of
TFA/CH2Cl2 (1:4) (20 mL), and stirred for 10 h at room temperature.
The mixture was basified with concentrated ammonia solution and
extracted with CH2Cl2 (3ꢂ15 mL). After the removal of the solvent
at reduced pressure, the residue was purified by recrystallization in
mixture hexane/ethyl acetate. Catalyst B was obtained in 71% yield;
mp 205e206 ꢁC. IR: 1660 cmꢀ1 (C]O). 1H NMR (400 MHz, CDCl3):
4.5.1. (S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one
(10a).20a,b It was obtained in a maximum of 95% yield and 90% ee.
anti/syn: 65:35, anti-diastereomer; 1H NMR (400 MHz, CDCl3
d
ppm): 1.29e2.09 (m, 6H), 2.30e2.47 (m, 2H), 2.55e2.61 (m, 1H),
4.10 (s, 1H), 4.87 (d, J¼8.4 Hz, 1H), 7.48 (d, J¼8.0 Hz, 2H), 8.16 (d,
J¼8.4 Hz, 2H). The optical purity was determined by HPLC on
Chiralpak AD-H column [hexane/2-propanol 90:10, 254 nm, flow
rate 0.5 mL/min], anti: tminor¼27.6 min and tmajor¼34.7 min.
4.5.2. (S)-2-((R)-Hydroxy(4-chlorophenyl)methyl)cyclohexan-1-one
(10b).20c It was obtained in a maximum of 78% yield and 72% ee.
anti/syn: 60:40, anti-diastereomer; 1H NMR (400 MHz, CDCl3
d
ppm): 1.25e2.12 (m, 6H), 2.30e2.50 (m, 2H), 2.52e2.60 (m, 1H),
d
(ppm): 1.04 (s, 18H, C(CH3)3), 1.24 (s, 18H, C(CH3)3), 1.56e2.09 (br
3.61 (s, 1H), 4.75 (d, J¼8.4 Hz, 1H), 7.25 (d, J¼8.4 Hz, 2H), 7.32 (d,
J¼8.7 Hz, 2H). The optical purity was determined by HPLC on
Chiralpak OD-H column [hexane/2-propanol 90:10, 220 nm, flow
rate 1.0 mL/min], anti: tmajor¼14.0 min and tminor¼20.9 min.
m, 8H, CH2CH2(proline)), 3.29e3.63 (br m, 16H, NCH2, ArCH2Ar),
4.07e4.14 (m, 2H, CH), 4.53 (d, J¼14 Hz, 4H, ArCH2Ar), 4.68 (s, 4H,
OCH2), 6.93 (s, 4H, ArH), 7.06 (s, 4H, ArH), 7.98e8.06 (m, 2H, NH),
9.01e9.13 (m, 2H, NH). 13C NMR (100 MHz, CDCl3): 173.3, 169.3,
149.4, 148.9, 148.2, 143.2, 132.3, 127.2, 126.2, 125.5, 74.7, 60.1, 46.7,
38.7, 34.1, 33.8, 32.1, 31.6, 31.0, 30.32, 25.5, 22.6, and 14.1. Anal. Calcd
for: C61H84O8N6: C, 71.18; H, 8.23; N, 8.16%. Found: C, 71.15; H, 8.22;
N, 8.14%.
4.5.3. (S)-2-((R)-Hydroxy(4-fluorophenyl)methyl)cyclohexan-1-one
(10c).20c It was obtained in a maximum of 83% yield and 77% ee.
anti/syn: 64:36, anti-diastereomer; 1H NMR (400 MHz, CDCl3
d
ppm): 1.25e1.33 (m, 1H), 1.52e1.81 (m, 4H), 2.06e2.11 (m, 1H),
2.35e2.58 (m, 3H), 4.02 (s, 1H), 4.78 (d, J¼8.8 Hz, 1H), 7.01e7.06
(m, 2H), 7.28e7.32 (m, 2H). The optical purity was determined by
HPLC on Chiralpak OD-H column [hexane/2-propanol 95:5,
220 nm, flow rate 0.5 mL/min], anti: tmajor¼27.06 min and
tminor¼47.4 min.
4.4. Synthesis of monomeric analog of catalyst A
Boc-L
-proline (1.24 g, 5.79 mmol) and N,N0-dicyclohex-
ylcarbodiimide (DCC) (1.2 g, 5.8 mmol) were dissolved in CH2Cl2
(20 mL) and cooled down to 0 ꢁC. After the solution was stirred for
30 min, a solution of compound 819 (1.0 g, 4.83 mmol) in
dichloromethane (50 mL) was added and the mixture was stirred
for 40 h at room temperature. Solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (100 mL) and the
organic layer extracted three times with water. The combined or-
ganic phases were dried (anhydrous MgSO4), the solvent was re-
moved under reduced pressure. Compound 9 was obtained in 77%
4.5.4. (S)-2-((R)-Hydroxy(4-bromophenyl)methyl)cyclohexan-1-one
(10d).20a,b It was obtained in a maximum of 84% yield and 80% ee.
anti/syn: 64:36, anti-diastereomer; 1H NMR (400 MHz, CDCl3
d
ppm): 1.22e1.33 (m, 1H), 1.51e1.80 (m, 3H), 2.06e2.11 (m, 1H),
2.30e2.57 (m, 3H), 4.02 (d, J¼2.7 Hz, 1H), 4.74 (dd, J¼8.7, 2.6 Hz,
1H), 7.20 (d, J¼8.4 Hz, 2H), 7.47 (d, J¼8.4 Hz, 2H). The optical purity
was determined by HPLC on Chiralpak AD-H column [hexane/2-
propanol 90:10, 220 nm, flow rate 0.5 mL/min], anti:
tminor¼34.4 min and tmajor¼36.1 min.
yield; 1H NMR (400 MHz, CDCl3):
d (ppm): 1.26 (s, 9H, C(CH3)3),1.43
(s, 9H, C(CH3)3), 1.51e2.31 (br m, 6H, CH2CH2(proline), OCH2CH2),
3.28e4.49 (br m, 7H, NHCH2(proline), NHCH2, OCH2, CH(proline)),
6.79 (br s, 2H, ArH), 7.26 (br s, 2H, ArH).
4.5.5. (S)-2-((R)-Hydroxy(3-chlorophenyl)methyl)cyclohexan-1-one
(10e).20d It was obtained in a maximum of 90% yield and 74% ee.
anti/syn: 62:38, anti-diastereomer; 1H NMR (400 MHz, CDCl3
Compound 9 (0.25 g, 0.62 mmol) was dissolved in a mixture of
TFA/CH2Cl2 (1:4) (20 mL), and stirred for 10 h at room temperature.
The mixture was basified with concentrated ammonia solution and
extracted with CH2Cl2 (3ꢂ15 mL). After the removal of the solvent
at reduced pressure, the residue was purified by recrystallization in
mixture hexane/ethyl acetate. Catalyst C was obtained in 75% yield;
d
ppm): 1.30e2.07 (m, 6H), 2.30e2.44 (m, 3H), 4.81 (d, J¼8.8 Hz,1H),
7.21e7.28 (m, 3H, Ar), 7.36 (s, 1H, Ar). The optical purity was de-
termined by HPLC on Chiralpak OD-H column [hexane/2-propanol
96:4, 220 nm, flow rate 1.0 mL/min], anti: tmajor¼15.0 min and
tminor¼20.4 min.
1H NMR (400 MHz, CDCl3):
d (ppm): 1.03 (s, 9H, C(CH3)3), 1.27e2.04
(br m, 6H, CH2CH2(proline), OCH2CH2), 2.87e4.02 (br m, 7H,
NHCH2(proline), NHCH2, OCH2, CH(proline)), 6.55 (br s, 2H, ArH),
7.01 (br s, 2H, ArH).
4.5.6. (S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one
(10f).20a It was obtained in a maximum of 80% yield and 82% ee.
anti/syn: 63:37, anti-diastereomer; 1H NMR (400 MHz, CDCl3
4.5. General procedure for the enantioselective direct aldol
reaction
d ppm): 1.33e2.13 (m, 6H), 2.32e2.51 (m, 2H), 2.60e2.66 (m, 1H),
4.14 (s, 1H), 4.88 (d, J¼8.4 Hz, 1H), 7.51 (t, J¼7.9 Hz, 1H), 7.65 (t,
J¼7.6 Hz, 1H), 8.14 (d, J¼7.9 Hz, 1H), 8.20 (d, J¼1.6 Hz, 1H). The
optical purity was determined by HPLC on Chiralpak OD-H column
[hexane/2-propanol 80:20, 254 nm, flow rate 0.5 mL/min], anti:
tmajor¼18.8 min and tminor¼24.4 min.
The following procedure for the reaction of cyclohexanone with
4-nitrobenzaldehyde in brine is representative.
In a typical experiment, a mixture of 4-nitrobenzaldehyde
(0.125 mmol), catalyst
(2.0 mmol) was stirred in water (250
A
(10 mol %), and cyclohexanone
L) at room temperature until
m
4.5.7. (S)-2-((R)-Hydroxy(2-chlorophenyl)methyl)cyclohexan-1-one
(10g).20d It was obtained in a maximum of 90% yield and 76% ee.
anti/syn: 60:40, anti-diastereomer; 1H NMR (400 MHz, CDCl3
the reaction was completed. This solution was extracted with
EtOAc. Then the organic layers were combined, dried with anhy-
drous Na2SO4, concentrated to dryness under reduced pressure,
and purified by preparative TLC. The absolute configuration of aldol
products was deduced by comparison of the HPLC retention times
with reported values. All the known aldol adducts matched the
reported characteristics. Characterization data for representative
examples are given below.
d
ppm): 1.50e2.09 (m, 6H), 2.28e2.47 (m, 2H), 2.62e2.70 (m, 1H),
3.91 (s, 1H), 5.33 (d, J¼8.0 Hz, 1H), 7.20 (t, J¼7.6 Hz, 1H), 7.28 (d,
J¼7.6 Hz, 1H), 7.30 (d, J¼8.1 Hz, 1H), 7.52 (d, J¼7.5 Hz, 1H). The
optical purity was determined by HPLC on Chiralpak OD-H column
[hexane/2-propanol 95:5, 220 nm, flow rate 1.0 mL/min], anti:
tmajor¼10.3 min and tminor¼12.9 min.

S. Eymur et al. / Tetrahedron 70 (2014) 4471e4477
4477
5. For recent reviews, see: (a) Mase, N.; Barbas, C. F., III. Org. Biomol. Chem. 2010, 8,
4043; (b) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687; (c) Gruttadauria, M.;
Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33; (d) Brogan, A. P.; Dick-
erson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45, 8100; (e) Hayashi, Y.
Angew. Chem., Int. Ed. 2006, 45, 8103.
6. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260; (b) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun. 2002, 3024; (c)
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C.; Pericas, M. Org. Lett. 2007, 9, 3717; (d) Blackmond, D. G.; Armstrong, A.;
Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798; (e) Hayashi, Y.;
Urushima, T.; Aratake, S.; Okano, T.; Obi, K. Org. Lett. 2008, 10, 21.
4.5.8. (S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one
(10h).8a It was obtained in a maximum of 78% yield and 83% ee.
anti/syn: 64:36, anti-diastereomer; 1H NMR (400 MHz, CDCl3
d
ppm): 1.50e1.78 (m, 6H), 2.26e2.41 (m, 2H), 2.70e2.74 (m, 1H),
4.05 (s, 1H), 5.40 (d, J¼7.2 Hz, 1H), 7.37 (t, J¼7.9 Hz, 1H), 7.56
(t, J¼7.7 Hz, 1H), 7.71 (d, J¼8.0 Hz, 1H), 7.75 (d, J¼8.0 Hz, 1H). The
optical purity was determined by HPLC on Chiralpak OD-H column
[hexane/2-propanol 80:20, 254 nm, flow rate 0.5 mL/min], anti:
tmajor¼16.2 min and tminor¼18.3 min.
8. (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2006, 128, 734; (b) Hayashi, Y.; Sumiya, T.; Takahashi, J.;
Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958; (c) Mase,
N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 4966; (e) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Su-
miya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527.
9. (a) Huang, J.; Zhang, X.; Armstrong, D. Angew. Chem., Int. Ed. 2007, 46, 9073; (b)
Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Meo, P. L.; Noto, R. Eur. J. Org.
Chem. 2010, 5696; (c) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687; (d)
Giacalone, F.; Gruttadauria, M.; Meo, P. L.; Riela, S.; Notoa, R. Adv. Synth. Catal.
2008, 350, 2747; (e) An, Y.-J.; Zhang, Y.-X.; Wua, Y.; Liu, Z.-M.; Pi, C.; Tao, J.-C.
Tetrahedron: Asymmetry 2010, 21, 688; (f) Hea, T.; Li, K.; Wua, M.-Y.; Wub, M.-B.;
Wang, N.; Pua, L.; Yua, X.-Q. Tetrahedron 2013, 69, 5136; (g) Doyaguez, E. Y.;
Mayoralas, A. F. Tetrahedron 2012, 68, 7345.
4.5.9. (S)-2-((R)-Hydroxy(4-methoxyphenyl)methyl)cyclohexan-1-
one (10i).20a,b It was obtained in a maximum of 40% yield and 50%
ee. anti/syn: 56:44, anti-diastereomer; 1H NMR (400 MHz, CDCl3
d
ppm): 1.44e1.50 (m, 1H), 1.63e1.81 (m, 3H), 2.07e2.12 (m, 1H),
2.30e2.61 (m, 4H), 3.81 (s, 3H), 3.92e3.94 (d, 1H, J¼2.4 Hz),
4.73e4.76 (dd, 1H, J¼1.6, 8.9 Hz), 6.87e6.89 (dd, 2H, J¼1.9, 6.7 Hz),
7.26 (d, 2H, J¼2.0 Hz). The optical purity was determined by
HPLC on Chiralpak OD-H column [hexane/2-propanol 90:10,
210 nm, flow rate 0.5 mL/min], anti: tmajor¼27.9 min and
tminor¼39.9 min.
10. (a) Joseph, R.; Rao, C. P. Chem. Rev. 2011, 111, 4658; (b) Calixarenes: A Versatile
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Class of Macrocyclic Compounds; Vicens, J., Bohmer, V., Eds.Topics in Inclusion
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The authors gratefully acknowledge the Scientific and Techno-
logical Research Council of Turkey (TUBITAK-Grant Number TBAG-
112T349), and Scientific Research Projects Foundation of Selcuk
University (SUBAP-Grant Number 14401006).
11. (a) Li, Z.-Y.; Chen, J.-W.; Wang, L.; Pan, Y. Synlett 2009, 2356; (b) Li, Z.-Y.; Chen,
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