Proline-calixarene thiourea host-guest complex catalyzed enantioselective aldol reactions: From nonpolar solvents to the presence of water

Article abstract of DOI:10.1016/j.tetasy.2014.01.015

A proline-calix[4]arene thiourea host-guest complex catalyzed intermolecular aldol reaction of aromatic aldehydes with cyclohexanone has been developed. The anti-configured products were obtained in good yields and with high enantioselectivities. The reac

Full text of DOI:10.1016/j.tetasy.2014.01.015

Tetrahedron: Asymmetry 25 (2014) 443–448
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Tetrahedron: Asymmetry
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Proline–calixarene thiourea host–guest complex catalyzed
enantioselective aldol reactions: from nonpolar solvents
to the presence of water
a,
Ezgi Demircan a, Serkan Eymur b, , Ayhan Sıtkı Demir
⇑
a Middle East Technical University, Department of Chemistry, 06800 Ankara, Turkey
b Selçuk 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:
Received 18 December 2013
Accepted 30 January 2014
A proline–calix[4]arene thiourea host–guest complex catalyzed intermolecular aldol reaction of aromatic
aldehydes with cyclohexanone has been developed. The anti-configured products were obtained in good
yields and with high enantioselectivities. The reaction is proposed to work via a modified Houk–List
model, where the carboxylate part of the proline constitutes as a supramolecular system with the thio-
urea. The outcome of the study indicates the influence of the calix[4]arene thiourea on both the reactivity
and selectivity in a non-polar reaction medium, even in the presence of water at moderate temperatures.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Shan et al. reported that using chiral diols as additives can improve
the enantioselectivity of proline catalyzed aldol reactions, possibly
The aldol reaction is one of the most commonly applied meth-
ods inspired by Nature, for CAC bond construction in synthetic or-
ganic chemistry.1 The catalytic potential of enamine catalysis with
through their involvement in the transition state, via the formation
of a hydrogen-bonding network.5 In 2007, Clarke et al. established
an enhancement in the reactivity and selectivity of a proline-
derived amide with a hydrogen bond acceptor site, which could
then self-assemble with hydrogen bond donor additives, thereby
turning a poor catalyst into a very good one via a Michael-type
addition of ketones to nitro olefins.6 Taking inspiration from the
use of supramolecular self-assembly units used by Clarke to make
a good asymmetric catalyst perfect, we have previously reported
the proof-of-principle results of proline-catalyzed direct aldol reac-
tions between cyclic ketones and aldehydes using Schreiner’s thio-
urea as the additive.7 We proposed that the reaction may proceed
according to a modified Houk–List model,8 in which the carboxyl-
ate moiety of the proline forms an assembly with the thiourea, in
turn enhancing the reactivity and selectivity of the catalyst.
Furthermore, the thiourea is treated as a non-polar counterpart
to proline, increasing its solubility limits in non-polar solvents,
such as hexane or toluene. Since then, great efforts have been made
to show the role of suitable additives in enhancing the reactivity
and stereoselectivity of the catalytic systems.9 These approaches
are clearly useful in avoiding tedious chemical syntheses and could
eventually allow the construction of libraries of structurally
diverse catalyst systems. Due to these features, there is still a con-
siderable demand for investigations into novel self-assembled
organocatalysts.
L
-proline, ‘the simplest enzyme’,2 for intermolecular enantioselec-
tive direct aldol reactions between unmodified ketones and
aldehydes was first introduced by List et al.3
L
-proline is environ-
mentally friendly, easily available, inexpensive, and easy to handle;
as a result, it is a first-choice catalyst for diastereo- and enantiose-
lective aldol reactions. Despite the fact that L-proline is still an
attractive organocatalyst, it has some potential issues such as (i)
limited reactivity and solubility in nonpolar organic solvents; (ii)
potential parasitic side reactions; and (iii) low selectivities with
aromatic aldehydes in direct aldol reactions.4 Although there have
been extensive efforts to develop new and efficient strategies
including new types of organocatalysts for improving the enanti-
oselectivities of the aldol reaction products, it is still a thriving area
in research.
After considerable efforts devoted to the development of pro-
line derivatives in order to improve their reactivity and selectivity,
it was found that the addition of catalytic or substoichiometric
additives as a cocatalyst allowed the introduction of new, effective,
and highly enantioselective organocatalytic systems. For instance,
⇑
Corresponding author. Tel.: +90 3322233887; fax: +90 332 2412499.
E-mail address: eymur@selcuk.edu.tr (S. Eymur).
Due to the advantages of water as compared to commonly used
organic solvents, reactions in aqueous media have recently
Deceased author (1950–2012).
http://dx.doi.org/10.1016/j.tetasy.2014.01.015
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

444
E. Demircan et al. / Tetrahedron: Asymmetry 25 (2014) 443–448
attracted a great deal of attention from a synthetic point of view in
recent years.10 In Nature, the hydrophobic active part of an enzyme
is responsible for the occurrence of the reactions in Class I Aldolase
type reactions.11 The hydrophobic ‘reaction flask’ of natural en-
zymes at their active site has inspired organic chemists to develop
entirely new hydrophobic proline derivatives as organocatalysts
for asymmetric aldol reactions ‘in the presence of water’.12 Under
such reaction conditions, the catalysts were used to promote the
reaction in a hydrophobic cavity, away from water molecules,
The hydrophobic cavities of calix[4]arenes make them good
candidates in host–guest chemistry due to possible noncovalent
interactions and the possibility of holding smaller molecules.
Therefore, the effect of calix[4]arene with a hydrophobic cavity
on the selectivity of the reaction in the presence of water was also
investigated.
2. Results and discussion
therefore giving better results than L-proline.
2.1. Synthesis of calix[4]arene derived achiral thiourea
Based on our previous research,7,13 we decided herein to
investigate direct asymmetric aldol reaction catalyzed by an
The (thio)urea functionalized calix[4]arene 5 was synthesized
from calixarene diamine 3 according to a procedure similar to that
reported for the synthesis of calix[4]arene derived thioureas.13 As
shown in Scheme 1, the synthesis commenced with the prepara-
tion of the bis(3-phthalimidopropoxy)calix[4]arene, which then
was transformed into the corresponding bis(3-aminoprop-
L-proline–calixarene-derived achiral thiourea host guest complex.
On this basis, it was thought that the hydrophobic cavity of ca-
lix[4]arene could be used for the reaction to proceed and increase
the solubility of proline with the help of thioureas attached to the
calix[4] arene molecule, which could also stabilize the transition
state due to hydrogen bonding interactions, which can be seen in
Figure 1.
oxy)calix[4]arene 3. Compound
3 was then reacted with
3,5-bis(trifluoromethyl)phenyl isothiocyanate to give (thio)urea
functionalized calix[4]arene 5.
2.2. Direct asymmetric aldol reaction in nonpolar solvents
alters the solubility problem
calixarene moiety
(CH2)3
Herein, we first report the ability of the proline–thiourea 5
host–guest catalyst in promoting enantioselective direct asymmet-
ric aldol reactions in nonpolar solvents, taking the reaction of
cyclohexanone and p-nitrobenzaldehyde as a model. To this end,
provides hydrophobic region
H
H
O
N
N
S
O
a
mixture of cyclohexanone (1 mmol), p-nitro-benzaldehyde
NH2
(0.5 mmol), and proline–thiourea 5 host–guest catalyst was stirred
in the corresponding solvent at ambient temperature for 24 h; the
results are shown in Table 1.
The reaction in DMSO, which is a classic polar solvent for this
type of reaction, furnished the same level of selectivity and product
CF3
F3C
Figure 1. Self-assembled organocatalyst.
KI, K2CO3
CH3CN
2. H2N-NH2/H2O
O
O
N
O
O
OH
OH
HO
OH
OH
OH
Br
H2N
NH2
1
2
3
S
C
F3C
N
THF, 0 o
C
O
O
OH
OH
O
O
OH
OH
CF3
4
HN
HN
NH
NH
S
H2N
S
NH2
CF3
F3C
F3C
CF3
5
Scheme 1. Synthetic pathway for the preparation of compound 5.

E. Demircan et al. / Tetrahedron: Asymmetry 25 (2014) 443–448
445
Table 1
Table 2
Optimization of the reaction conditions for the direct enantioselective aldol reaction
of cyclohexanone with p-nitrobenzaldehyde catalyzed by proline/thiourea 5
L-Proline/thiourea
presence of water
5 host guest complex catalyzed direct aldol reactions in the
O
O
O
O
O
OH
O
OH
L-proline (10%)
L-proline
H
thiourea 5 (5%)
H
thiourea 5
water, r.t., 24 h
solvent, r.t., 24h
O2N
O2N
NO2
NO2
Entry
Water
(equiv)
Cyclohexanone
(equiv)
Yielda
(%)
anti:synb
eec
(%)
Entry
Solvent
Catalysta (%)
Yieldb (%)
anti:sync
eed (%)
1
2
3
4
5
6
7
8
MeCN
CHCl3
CH2Cl2
Toluene
Cyclohexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
10:5
10:5
10:5
10:5
10:5
20:20
20:10
10:10
10:5
5:5
32
90
87
95
95
97
97
97
99
45
82
36
68:32
80:20
77:23
87:13
88:12
90:10
86:14
88:12
95:5
90
92
89
90
92
91
96
96
99
98
89
84
1
2
3
4
18
18
9
36
108
18
8
3
3
3
3
3
51
60
54
35
Trace
Trace
52:48
65:35
54:46
52:48
n.d
80
92
88
82
n.d
n.d
5
6d
n.d
a
b
c
Isolated yield after flash column chromatography on silica gel.
Determined by 1H NMR of the crude mixture.
The ee value of the anti-isomer was determined by chiral HPLC analysis in
9
10
11e
12f
90:10
88:12
77:23
10:5
10:5
comparison with an authentic racemic material.
d
Schreiner’s thiourea was used.
a
L
-Proline:thiourea 5 (mol %).
b
c
Isolated yield after flash column chromatography on silica gel.
Determined by 1H NMR of the crude mixture.
of the donor were used, and good results were obtained with 60%
yield and 92% ee, although the dr value was moderate (65:35)
(Table 2, entry 2). The reaction yield decreased sharply when a
large excess of water was used (Table 2, entries 4 and 5). Tolerable
results were also obtained when 9 equiv of water were used
(Table 2, entry 3). It was also shown that the reaction did not
take place when 1,3-bis(3,5-bis(trifluoromethyl)phenyl) thiourea
(Schreiner’s thiourea) was used, which clearly demonstrated the
importance of the hydrophobic part of the calix[4]arene skeletons
in compound 5, for the reaction to proceed in the presence of
water.
With these optimized conditions in hand, the scope and limita-
tions of the direct asymmetric aldol reactions between a series of
aromatic aldehydes and cyclohexanone were examined (Table 2).
We chose nitro, cyano, trifluoromethyl, and halogen substituents
as demonstrative electron-withdrawing groups and a methoxy
substituent as an electron-donating group on the phenyl ring.
As can be seen in Table 3, using hexane as the solvent, the reac-
tions between aromatic aldehydes with electron-withdrawing and
donating substituents on the phenyl ring and cyclohexanone
resulted in the corresponding anti-aldol products with good to
excellent diastereoselection and with 80–99% ee (Table 2, Method
A). With the exception of the cyano substituent, electron-with-
drawing groups generally gave excellent enantioselectivity.
An electron-donating methoxy group at the para-position on
the phenyl ring decreased the reaction rate and both the
diastereoselectivty and enantioselectivty (entry 9).
d
The ee value of the anti-isomer was determined by chiral HPLC analysis in
comparison with an authentic racemic material.
e
(S)-tert-Leucine was used as the catalyst.
(S)-Tryptophan was used as the catalyst.
f
purity with or without the urea additive. When MeCN was used,
the reaction was slow and the selectivity was low (Table 1, entry
1). This was, of course, not unexpected when considering the pos-
sibility of hydrogen bonding in polar solvents.
When we moved to non-polar solvents, both the efficiency and
selectivity were enhanced remarkably. The results show that the
optimum conditions, in terms of stereoselection and chemical
yield, were obtained with hexane. Thiourea functionalized
calix[4]arene 5 loading was also found to be critical for high
enantioselectivity. With greater than 20 mol % loading, poorer
enantioselectivities of the products were obtained. For example,
with a 20 mol % loading, an enantiomeric excess of 91% was
obtained for the para-NO2 derivative (Table 1, entry 7); a similar
reaction with 5 mol % loading produced a product with 99% ee
(Table 1, entry 6). The optimum amount of catalyst (proline:thio-
urea 5) was determined as 10:5 (%) relative to the aldehyde, and
afforded the product with high yield and stereoselectivity (Table 1,
entry 9).
We also found that primary amino acids such as (S)-tryptophan
and (S)-tert-leucine were very good catalysts for this transforma-
tion (Table 1, entries 7 and 8), although proline was superior. These
results evidently show the great effect of the thiourea moiety on
the reactivity and selectivity, even in an unconventional nonpolar
reaction medium, without the need to use low temperatures. It is
also noteworthy that the sense of stereoselection is the same as
that with proline as the sole catalyst.
Moreover, we also studied the reactions between aldehydes and
cyclohexanone in the presence of water (Table 2, Method B). The
reaction of aromatic aldehydes with electron withdrawing groups
proceeded smoothly and were completed in 24 h with isolated
yields ranging from 48% to 62% and with up to 92% ee.
2.3. Direct asymmetric aldol reaction in the presence of water
All of the aforementioned results led us to propose a mecha-
nism based on general enamine catalysis. The transition state can
be explained according to a modified Houk–List model,8a,b because
thiourea generates a supramolecular unit due to hydrogen bonding
with the carboxylic acid moiety of the proline, which participates
in improving the catalytic properties of proline (Fig. 2, Model A).
Furthermore, the hydrogen on the amine moiety of the proline be-
comes much more acidic, which also assists in stabilizing the tran-
sition state. Furthermore, the chair conformation in the transition
state explains the stability and stereoselectivity seen in the reac-
tion. Lastly, a nonpolar thiourea moiety helps to increase the solu-
bility properties of proline in non-polar solvents such as hexane or
toluene.
Using water as the reaction medium, we decided to investigate
the effect of the hydrophobic part of the calix[4]arene moiety of
the thiourea guest molecule. For this purpose, the reaction of cyclo-
hexanone and 4-nitrobenzaldehyde was tested in the presence of
water under various conditions (Table 2).
As summarized in Table 2, when 18 equiv of water and 8 equiv
of donor were employed, the reaction proceeded efficiently to give
the aldol product in 51% yield, with a dr of 52:48 in favor of the anti
stereochemistry and 80% ee (Table 2, entry 1). From a practical
point of view, the direct asymmetric aldol reaction usually requires
a large (16-fold) excess of the donor. However, herein only 3 equiv.

446
E. Demircan et al. / Tetrahedron: Asymmetry 25 (2014) 443–448
Table 3
3. Conclusion
Aldol reaction of different aldehydes with cyclic ketones catalyzed by L-proline/
thiourea 5
In conclusion, we have shown that the host–guest proline–
thiourea functionalized calix[4]arene 5 complex can directly cata-
lyze enantioselective aldol reactions in nonpolar solvents. Under
the optimal conditions, high yields (up to 95%), enantioselectivities
(up to >99% ee), and diastereoselectivities (up to 97:3) were
obtained. The reaction is proposed to proceed via a modified
Houk–List model, where the carboxylate part of the proline consti-
tutes a supramolecular system with the thiourea. We have also
found that these self-assembled organocatalysts can catalyze di-
rect aldol reactions in the presence of water with moderate diaste-
reoselectivities (up to 65:35) and with high enantioselectivities (up
to 92% ee). Considering the catalytic inefficiency of proline for the
aldol reaction in water, these results clearly demonstrate the effect
of the hydrophobic part of calix[4]arene thiourea 5 on both reactiv-
ity and selectivity, in the presence of water, without the need to
use low temperatures.
O
O
OH
O
L-proline (10%)
thiourea 5 (5%)
R
R
H
hexane (or water)
r.t., 24h
7
6
8a-i
Entrya
1
Aldehyde (R)
Yieldb (%)
anti:sync
eed (%)
4-NO2Ph (A)
(B)
95
60
80
55
78
53
78
58
90
60
90
62
83
54
84
50
70
30
97:3
65:35
94:6
62:38
80:20
59:41
94:6
60:40
94:6
58:42
96:4
60:40
96:4
62:38
90:10
61:39
81:19
53:47
99
92
99
81
87
81
95
80
99
86
99
87
99
77
94
82
80
35
2
3
4
5
6
7
8
9
4-BrPh (A)
(B)
4-CNPh (A)
(B)
4-CF3Ph (A)
(B)
3-CF3Ph (A)
(B)
3-NO2Ph (A)
(B)
4. Experimental
4.1. General
2-BrPh (A)
(B)
2-FPh (A)
(B)
4-MeOPh (A)
(B)
NMR spectra were recorded on a Bruker DPX 400. 1H NMR
spectra are reported in ppm using solvent as an internal standard
(CHCl3 at 7.26 ppm). Data are reported as (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet; coupling constant(s) in Hz;
integration. Proton-decoupled 13C NMR spectra were recorded
on a 100 MHz spectrometer and are reported in ppm using solvent
as an internal standard (CDCl3 at 77.0 ppm). Column chromatog-
a
b
c
(A): Method A (in hexane), (B): Method B (in the presence of water).
Isolated yield after flash column chromatography on silica gel.
Determined by 1H NMR of the crude mixture.
d
The ee value of the anti-isomer was determined by chiral HPLC analysis in
comparison with an authentic racemic material.
raphy was conducted on silica gel 60 (mesh size 40–63 lm). TLC
When the reaction was performed in the presence of water, we
again assumed that the asymmetric aldol reaction occurred via an
enamine mechanism (Fig. 2, Model B). As depicted in Figure 2,
Model B, a hydrophobic region and a hydrophilic region can be
created by the formation of hydrogen bonds between free OH
groups of interfacial water molecules and OH groups of the calixa-
rene moiety, which enhances the activity of organic catalysis on
water.
was carried out on aluminum sheets precoated with silica gel
60F254 (Merck). Visualization was accomplished with UV light
and anisaldehyde followed by heating. HRMS were recorded on
Agilent 6224 TOF LC/MS. The enantiomeric excess (ee) of the
products was determined by chiral-phase HPLC analysis. Optical
rotations were measured with a Kru¨ss P3002RS automatic polar-
imeter at 589 nm.
Model A
Model B
Ar
Ar
O
H
O
H
N
N
H
S
O
S
O
O
H
H
N
N
NH2
NH2
O
H
O
O
O
H
H
H
H
hydrophilic
region
H
O
O
hydrophobic
region
O
O
O
O
O
H2O
H
H
O
N
N
H
H
S
S
O
O
O
H
N
N
H
H
Ar
Ar
O
H
O
H
Ar: 3,5-CF3C6H4
NH2
NH2
Figure 2. The proposed interaction of the thiourea moiety with proline (a) in nonpolar solvents and (b) in the presence of water.

E. Demircan et al. / Tetrahedron: Asymmetry 25 (2014) 443–448
447
4.2. Synthesis of p-tert-butyl calix[4]arene thiourea 3
98% ee};15b anti/syn: 94/6, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 1.37–1.21 (m, 1H), 1.62–1.54 (m, 3H), 1.86–1.75
(m, 1H), 2.15–2.04 (m, 1H), 2.34 (d, J = 7.2 Hz, 1H), 2.64–2.43 (m,
2H), 3.98 (d, J = 2.72 Hz, 1H), 4.75 (d, J = 8.7 Hz, 1H), 7.20 (d,
J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H) 99% ee was obtained. The
enantiomeric purity was determined by HPLC on a chiralpak AD-
H column [hexane/2-propanol 90:10]; flow rate 1.0 mL/min, anti:
tmajor = 14.4 min and tminor = 16.7 min.
p-t-Butylcalix[4]arene diamine (1.0 mmol, 0.762 mg) was dis-
solved in 30 ml of dried THF. Then, 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (2.2 mmol, 400 lL) was added via syringe in an ice
bath and the mixture was stirred at room temperature until the
completion of the reaction (monitored by TLC). After completion
of the reaction, the volatile material was removed and the remain-
ing solid was dissolved in a minimum amount of EtOAc. By using
column chromatography, the desired product was taken in a 4:1
(Hexane/EtOAc) solvent system. Finally, n-hexane was added for
precipitation. The solid product was filtered and washed with
hexane several times. The crystallization procedure was then
applied to the filtered product. 1H NMR (400 MHz, CDCl3 d ppm):
9.17–9.07 (m, 2H), 7.87–7.85 (m, 4H), 7.81–7.74 (m, 2H), 7.61–
7.57 (m, 2H), 7.57–7.53 (m, 2H), 7.18–7.16 (m, 4H), 6.86–6.81
(m, 4H), 4.10–3.97 (m, 12H), 3.51–3.39 (m, 4H), 2.24–2.03 (m,
4H), 1.35–1.27 (m, 18H), 0.99–0.93 (m, 18H) 13C NMR (101 MHz,
CDCl3 d ppm): 181.6, 148.6, 148.5, 148.0, 144.7, 140.4, 132.0,
131.7, 126.18 126.2, 124.4, 122.7, 117.9, 44.7, 34.1, 31.9, 30.9,
28.3. HRMS: Calculated mass: 1304.2003 g/mole Measured
[MꢀH]+: 1305.5212 g/mole.
4.3.3. 4-[Hydroxy(2-oxocyclohexyl)methyl]benzonitrile 8c14a
This compound was obtained in a maximum of 78% yield and
87% ee; ½a rDt
ꢁ
¼ þ19:2 (c 1.0 CHCl3) {lit. ½a D25
¼ þ20:1 (c 1.4, CHCl3)
ꢁ
85% ee};15c anti/syn: 80/20, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 1.43–1.30 (m, 1H), 1.64–1.51 (m, 1H), 1.90–1.77
(m, 1H), 2.16–2.07 (m, 1H), 2.42–2.30 (m, 1H), 2.62–2.45 (m,
1H), 4.07 (d, 1H), 4.84 (d, J = 8.5 Hz, 1H), 7.46–7.43 (m, 2H),
7.68–7.63 (m, 1H). The enantiomeric purity was determined by
HPLC on a chiralpak AD-H column [hexane/2-propanol 90:10];
flow rate 1.0 mL/min, anti: tmajor = 24.5 min and tminor = 31.1 min.
4.3.4. (S)-2-((R)-Hydroxy(4-trifluoromethylphenyl)methyl)cyc-
lohexan-1-one 8d14b
This compound was obtained in a maximum of 78% yield and
4.3. General procedure for the enantioselective direct aldol
Reaction
95% ee; ½a rDt
ꢁ
¼ þ2:3 (c 1.0 CHCl3) {lit. ½a D25
¼ þ2:8 (c 1.3, CHCl3
ꢁ
99% ee)};15c anti/syn: 94/6, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 1.66–1.51 (m, 4H), 1.86–1.76 (m, 1H), 2.16–2.05
(m, 1H), 2.43–2.31 (m, 1H), 2.54–2.44 (m, 1H), 2.66–2.55 (m,
1H), 4.04 (d, J = 2.8 Hz, 1H), 4.85 (d, J = 8.6 Hz, 1H), 7.45 (d,
J = 8.0 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H). The enantiomeric purity
was determined by HPLC on a chiralpak OD-H column [hexane/2-
propanol 95:5]; flow rate 0.5 mL/min, anti: tmajor = 11.5 min and
tminor = 14.9 min.
Method A:
L-Proline (0.025 mmol, 2.8 mg), calix[4]arene thio-
urea (0.0125 mmol, 16.25 mg), and 45
l
L of hexane were placed
in a screw capped vial, then cyclohexanone (2 mmol, 0.2 mL) was
added, in which the resulting mixture was stirred for 15 min. at
ambient temperature followed by the addition of aldehyde
(0.25 mmol) after which stirring was continued until no further
conversion was observed by TLC. After completion of the reaction,
the reaction mixture was treated with saturated aqueous ammo-
nium chloride solution and the whole mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried, and
concentrated to give a crude residue, which was purified by col-
umn chromatography over silica gel using hexane–ethyl acetate
as an eluent to afford a pure product.
4.3.5. (S)-2-((R)-Hydroxy(3-trifluoromethylphenyl)methyl)cyc-
lohexan-1-one 8e14c,d
This compound was obtained in a maximum of 90% yield and
99% ee; ½a rDt
ꢁ ¼ þ10:2 (c 1.0 CHCl3); anti/syn: 94/6, anti-diastereo-
mer, 1H NMR (400 MHz, CDCl3 d ppm): 1.33–1.14 (m, 2H), 1.68–
1.55 (m, 2H), 1.80–1.69 (m, 1H), 2.10–1.99 (m, 1H), 2.37–2.24
(m, 1H), 2.47–2.37 (m, 1H), 2.59–2.5 (m, 1H), 4.01 (d, 1H(syn)),
4.77 (d, J = 8.7 Hz, 2H), 7.46–7.37 (m, 1H), 7.55–7.47 (m, 2H) The
enantiomeric purity was determined by HPLC on a chiralpak
AS-H column [hexane/2-propanol 95:5]; flow rate 0.5 mL/min,
anti: tmajor = 19.6 min, tminor = 23.8 min.
Method B: At first, L-proline (0.025 mmol, 2.8 mg), calix[4]arene
thiourea (0.0125 mmol, 16.25 mg) and 45 mL of hexane were
placed in a screw capped vial, then cyclohexanone (0.75 mmol,
75 lL) was added, in which the resulting mixture was stirred for
15 min at ambient temperature followed by the addition of alde-
hyde (0.25 mmol) after which stirring was continued until no fur-
ther conversion was observed by TLC. After completion of the
reaction, work-up was carried out in the usual manner as described
above.
4.3.6. (S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-
one 8f14a
This compound was obtained in a maximum of 90% yield and
99% ee; ½a rDt
ꢁ
¼ þ38:4 (c 1.0 CHCl3) {lit. ½a Drt
ꢁ ¼ þ37:6 (c 1.0, CHCl3)
4.3.1. (S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-
one 8a14a,b
96% ee};15b anti/syn: 96/4, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 1.47–1.32 (m, 1H) 1.76–1.51 (m, 4H), 1.91–1.78
(m, 1H), 2.17–2.07 (m, 1H), 2.44–2.31 (m, 1H), 2.56–2.46 (m, 1H),
2.72–2.58 (m, 1H), 4.13 (d, J = 3.0 Hz, 1H), 4.91 (d, J = 8.5 Hz, 1H),
7.54 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 8.16 (d, J = 8.2 Hz,
1H), 8.22 (s, 1H). The enantiomeric purity was determined by HPLC
on a chiralpak AD-H column [hexane/2-propanol 90:10]; flow rate
1.0 mL/min, anti: tmajor = 19.9 min. and tminor = 25.2 min.
This compound was obtained in a maximum of 95% yield and
99% ee; ½a rDt
ꢁ
¼ þ11:5 (c 1.0 CHCl3) {lit. ½a Drt
ꢁ ¼ þ11:8 (c 1.0, CHCl3)
95% ee};15a anti/syn: 97/3, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 1.46–1.31 (m, 1H), 1.71–1.52 (m, 3H), 1.93–1.77
(m, 1H), 2.16–2.07 (m, 1H), 2.42–2.31 (m, 1H), 2.54–2.45 (m,
1H), 2.66–2.55 (m, 1H), 4.09 (s, 1H), 4.90 (d, J = 8.3 Hz, 1H), 7.51
(d, J = 8.6 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H). The enantiomeric purity
was determined by HPLC on a chiralpak AD-H column [hexane/2-
propanol 90:10]; flow rate 1.0 mL/min, anti: tminor = 24.6 min and
tmajor = 32.3 min
4.3.7. (S)-2-((R)-Hydroxy(2-bromophenyl)methyl)cyclohexan-1-
one 8g14e
This compound was obtained in a maximum of 83% yield and
99% ee; ½a rDt
ꢁ
¼ þ20:2 (c 1.0 CHCl3) {lit. ½a D25
¼ þ20:1 (c 0.5, CHCl3)
ꢁ
4.3.2. (S)-2-((R)-Hydroxy(4-bromophenyl)methyl)cyclohexan-1-
one 8b14a,b
97% ee)};15b anti/syn: 96/4, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 2.14–2.05 (m, 1H), 2.41–2.28 (m, 1H), 2.52–2.41
(m, 1H), 2.76–2.62 (m, 1H), 4.04 (d, J = 4.09 Hz, 1H), 5.30 (dd,
J = 7.96 Hz, 1H), 7.13 (t, J = 7.44 Hz, 1H), 7.34 (t, J = 7.70 Hz, 1H),
This compound was obtained in a maximum of 80% yield and
99% ee; ½a rDt
ꢁ
¼ þ11:5 (c 0.8 CHCl3) {lit. ½a Drt
ꢁ ¼ þ11:3 (c 1.0, CHCl3)

448
E. Demircan et al. / Tetrahedron: Asymmetry 25 (2014) 443–448
2. Movassaghi, M.; Jabocsen, E. N. Science 2002, 298, 1904.
7.52 (d, J = 7.97 Hz, 1H). The enantiomeric purity was determined
by HPLC on a chiralpak AD-H column [hexane/2-propanol 90:10];
flow rate 0.3 mL/min, anti: tmajor = 37.2 min. and tminor = 43.5 min.
3. (a) List, B.; Lerner, A. R.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395; For
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4.3.8. (S)-2-((R)-Hydroxy(2-fluorophenyl)methyl)cyclohexan-1-
one 8h14f
This compound was obtained in a maximum of 84% yield and
94% ee; ½a rDt
ꢁ
¼ þ20:8 (c 1.0 CHCl3) {lit. ½a D25
¼ þ22:6 (c 0.6, CHCl3)
ꢁ
99% ee};15d anti/syn: 90/10, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 2.42–2.30 (m, 1H), 2.53–2.44 (m, 1H), 2.75–2.60
(m, 1H), 3.99 (d, J = 3.4 Hz, 1H), 5.18 (d, J = 8.7 Hz, 1H), 7.06–6.97
(m, 1H), 7.21–7.13 (m, 1H), 7.30–7.23 (m, 1H), 7.53–7.43 (m,
1H). The enantiomeric purity was determined by HPLC on a chir-
alpak AD-H column [hexane/2-propanol 95:5]; flow rate 1.0 mL/
min, anti: tmajor = 8.9 min and tminor = 12.0 min.
4.3.9. (S)-2-((R)-Hydroxy(4-methoxyphenyl)methyl)cyclohexan-
1-one 8i14a,b
This compound was obtained in a maximum of 70% yield and
80% ee; ½a rDt
ꢁ
¼ þ26:3 (c 1.0 CHCl3) {lit. ½a D25
¼ þ30:5 (c 1.7, CHCl3)
ꢁ
91% ee};15c anti/syn: 81/19, anti-diastereomer, 1H NMR (400 MHz,
CDCl3 d ppm): 1.43–1.51 (m, 1H), 1.63–1.82 (m, 3H), 2.07–2.11
(m, 1H), 2.30–2.61 (m, 4H), 3.81 (s, 3H), 3.92–3.94 (d, 1H,
J = 2.4 Hz), 4.73–4.76 (dd, 1H, J = 1.6, 8.9 Hz), 6.87–6.89 (dd, 2H,
J = 1.9, 6.7 Hz), 7.25 (d, 2H, J = 2.0 Hz). The enantiomeric purity
was determined by HPLC on a chiralpak AD-H column [hexane/2-
propanol 95:5]; flow rate 0.8 mL/min, anti: tmajor = 30.1 min and
tminor = 31.7 min.
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Asymmetry 2007, 18, 265.
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Acknowledgments
The authors gratefully acknowledge the Scientific and Techno-
logical Research Council of Turkey (TUBITAK), Selçuk University
and The Middle East Technical University (METU). The authors also
thank Professor Abdulkadir Sırıt for providing the bis(3-amino-
propoxy)calix[4]arene 3.
References
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