Upper rim-functionalized calix[4]arene-based l-proline as organocatalyst for direct asymmetric aldol reactions in water and organic media

Article abstract of DOI:10.1016/j.tet.2014.10.063

The synthesis of upper rim-functionalized calix[4]arene-based l-proline was described, and its catalytic efficiency as organocatalyst for the enantioselective aldol reaction in water was investigated. The results showed that the nature of the hydrophobic

Full text of DOI:10.1016/j.tet.2014.10.063

Accepted Manuscript
Upper rim functionalized calix[4]arene-based L-proline as organocatalyst for direct
asymmetric aldol reactions in water and organic media
Arzu Uyanik, Mevlut Bayrakci, Serkan Eymur, Mustafa Yilmaz
PII:
S0040-4020(14)01514-2
10.1016/j.tet.2014.10.063
TET 26133
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 August 2014
Revised Date: 15 October 2014
Accepted Date: 27 October 2014
Please cite this article as: Uyanik A, Bayrakci M, Eymur S, Yilmaz M, Upper rim functionalized
calix[4]arene-based L-proline as organocatalyst for direct asymmetric aldol reactions in water and
organic media, Tetrahedron (2014), doi: 10.1016/j.tet.2014.10.063.
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ACCEPTED MANUSCRIPT
Upper rim-functionalized calix[4]arene-based L-proline as organocatalyst for
direct asymmetric aldol reactions in water and organic media
Graphical Abstract:
O
O
OH
O
Catalyst (10% mol)
Water, r.t., 24 h
R
R
H
Up to 94% yield, 95:5 dr, 80% ee
OH
OH
HO
HO
Catalyst:
NH
HN
2
NH
OH
HN
HO
O
O

ACCEPTED MANUSCRIPT
Upper rim functionalized calix[4]arene-based L-proline as
organocatalyst for direct asymmetric aldol reactions in water and
organic media
Arzu Uyanika, Mevlut Bayrakcib, Serkan Eymura,c*, Mustafa Yilmaza*
aSelcuk University, Department of Chemistry, 42031 Konya, Turkey
bNigde University, Ulukisla Vocational School, 51100 Nigde, Turkey
cGiresun University, Department of Energy Systems Engineering, 28200 Giresun,
Turkey
Abstract
The synthesis of upper rim-functionalized calix[4]arene-based L-proline was
described, and its catalytic efficiency as organocatalyst for the enantioselective aldol
reaction in water was investigated. The results showed that the nature of the
hydrophobic cavity of calixarene is critical for catalytic activity in water. The
products of the reaction between various ketones and aldehydes with anti-
configuration were obtained in high yields (up to 94%) with high diastereo- (up to
95:5 dr) and enantioselectivities (up to 80% ee).
1. Introduction
The synthesis of enantiomerically pure compounds has attracted extensive
interest in academic and especially commercial communities because enantiomers of
the same compound can show different biological activities.1 In recent years,
enantioselective C-C bond formation reactions catalyzed by organocatalysts have
been recognized as powerful tools for creating practical protocols for asymmetric
organic synthesis.2 The organocatalytic aldol reaction is one of the most powerful C-C
bond-forming processes, yielding 1,3-dioxygenated compounds, which are important
structural motifs found in biologically active molecules.3 After the seminal
contributions of List et al. in the early 2000s,4 L-proline and its various structural
derivatives were shown to be powerful catalysts in asymmetric aldol reactions.5
Corresponding author. Tel.: +90 454 3101375; e-mail: serkan.eymur@giresun.edu.tr

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Over the past few decades, the use of water as a reaction medium for
enantioselective transformations has attracted significant attention from a synthetic
point of view, because water possesses unique and attractive properties as a solvent
that alter the reactivity of catalysts and help generate intermediate transition states
during catalytic processes.6 Although L-proline derivative-catalyzed organocatalytic
aldol reactions are typically performed in polar organic solvents such as DMSO or
DMF, it has been demonstrated that the addition of a small amount of water has a
positive effect on the reaction.7 However, the use of an excess amount of water
decreases the reactivity and stereocontrol of the reaction.8 Therefore, the investigation
of novel chiral molecules capable of promoting enantioselective aldol reactions in
water remains an important goal. For this purpose, the catalytic efficiency of L-
proline derivatives bearing large apolar substituents and amine catalysts bearing
hydrophobic alkyl chains for highly diastereo- and enantioselective direct aldol
reactions in water have recently been investigated by several research groups.9
Calixarenes are macrocyclic, basket-like compounds that are important in
supramolecular chemistry mostly due to their potential ability to exist in a cone
conformation, and the ease with which their lower and upper rims can be functionally
modifed.10 In particular, calix[4]arene derivatives have been used successfully in the
areas of ion and molecular recognition, host-guest chemistry, catalysis, enzyme
mimicry, interaction with biomolecules, ion extraction and selective ion transport
systems.11
We have recently reported a direct aldol reaction in water using p-tert-
butylcalix[4]arene-based chiral organocatalysts bearing a chiral proline moiety at the
lower rim of the calix[4]arene units (1, Figure 1).12 We postulated that a hydrophobic
region and a hydrophilic region can be generated by the formation of hydrogen bonds
between the free OH groups of interfacial water molecules and the OH groups of the
calix[4]arene moiety, and catalyst 1 should assemble with hydrophobic reactants in
water and isolate the transition state from water. When considering the catalytic
inefficiency of the monomeric analog of compound 1 for the aldol reaction in water,
we can easily assume that the hydrophobic part of the lower rim-functionalized
calix[4]arene of compound 1 is responsible for the observed reactivity and selectivity
in water. In this study, we aimed to synthesize a novel upper rim-functionalized
calix[4]arene-based L-proline compound 2 to catalyze direct aldol reactions between
cyclohexanone and aromatic aldehydes in water.

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O
O
OH
HO
HN
NH
O
O
HO
O
HO
NH
HN
HN
HN
NH
NH
HN
HN
O
O
O
OH OH
HO
OH
2
1
Monomeric analog of 1
Efficient organocatalyst
for aldol reactions in water
Inefficient organocatalyst
Upper rim functionalized calixarene
Lower rim functionalized calixarene
Our Previous study
This study
Figure 1. Structure of proline-substituted calixarene derivatives as catalysts for aldol
reactions in water.
2. Results and discussion
We have a keen interest in asymmetric aldol reactions that can be promoted by
calix[4]arene-based organocatalysts. In this study, our aim was to develop a novel
upper rim-functionalized calix[4]arene-based organocatalyst for enantioselective aldol
reactions in water. As far as we know, there has been only one report of a compound
of this class in the literature,13 in which an L-proline moiety was introduced
selectively at the upper rim of conformationally rigid calix[4]arenes. This
organocatalyst had been evaluated in enantioselective aldol reactions in the presence
of only small amounts of water, affording moderate enantiomeric excesses (ees up to
49%). Therefore, the investigation of novel calixarene-based organocatalysts for aldol
reactions in water is still emerging and deserves more attention. Encouraged by our
previous experience with direct asymmetric aldol reactions catalyzed by lower rim-
functionalized calixarenes in water,12 we hypothesized that an upper rim-
functionalized calix[4]arene-based L-proline might also be a simple and efficient
catalyst for aldol reactions in water. In the work presented here, we report a direct
catalytic asymmetric aldol reaction with cyclohexanone as the aldol donor catalyzed
by upper rim-functionalized calix[4]arene-based organocatalyst 2.

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2.1 Synthesis of Catalyst 2
The synthesis of organocatalyst 2 investigated in this study is summarized in
Schemes 1 and 2. The required starting materials 4-8 were obtained according to
published procedures as shown in Scheme 1.14-16
OH
Ph
Ph
O
O
OH
O
OH
OH
HO
HO
OH
OH
OH
O
OH
HO
ii
i
4
4
3
4
5
iii
Ph
Ph
O
O
O
OH
HO
OH
OH
OH
O
HO
HO
HO
OH
HO
v
iv
Cl
Cl
7
8
6
Scheme 1. Synthesis of the compound 8 Reaction conditions: (i): HCOH, NaOH, 2h,
110-120 °C, (ii): K2CO3, benzoyl chloride, CH3CN, 4h, 80 °C, (iii): AlCl3, toluene,
2h, room temperature, (iv): NaOH, ethanol/water, 12h, reflux, (v): C8H17OCH2Cl,
SnCl4, chloroform, -10 °C.
Next, L-proline-substituted calix[4]arene derivatives 9, 10 and 2 were
obtained in three steps (Scheme 2); these derivatives have not been synthesized
previously. As shown below, chloromethylated compound 8 was stirred overnight
with N-Boc-trans-4-amino-L-proline methyl ester hydrochloride in the presence of
triethylamine to obtain the corresponding Boc-protected proline methyl ester of
calix[4]arene 9. In the second step, the methyl ester of calix[4]arene 9 was
subsequently converted into the carboxylic acid analogue 10 by the reaction of the
Boc-protected proline methyl ester of calix[4]arene 9 with NaOH and methanol at
room temperature under a dry atmosphere. Finally, the Boc groups of calixarene 10
were converted to the final compound 2 by the controlled hydrolyzation of crude
product 10 with trifluoroacetic acid (TFA).

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O
OH
HO
HO
OH
O
OH
HO
HO
OH
O
O
HCl
H2N
N
i
NH
HN
Cl
Cl
2
2
BOC
N
N
BOC
9
O
CH3
8
O
H3C
O
O
ii
OH
HO
OH
HO
HO
OH
HO
OH
iii
NH
NH
HN
HN
2
2
NH
OH
BOC
N
HN
HO
N
BOC
2
10
OH
HO
O
O
O
O
Scheme 2. Synthesis of the compound 2 Reaction conditions: (i): TEA,
dichloromethane, overnight, room temperature, (ii): 2M NaOH, MeOH, 15h, room
temperature, (iii): TFA, CH2Cl2, overnight, room temperature.
All of the compounds were fully characterized by 1H, 13C NMR, FT-IR (ATR)
1
spectroscopy and elemental analyses. The H NMR spectra of newly synthesized
compounds 2, 8, 9, and 10 showed two sets of doublets corresponding to the bridging
methylene protons. A typical AX pattern was observed around 3.20-3.40 ppm and
4.10-4.20 ppm, corresponding to the methylene bridge ArCH2Ar protons for
compounds 9, 10 and 2. The high field doublets around 3.20–3.40 ppm for
compounds 9, 10, and 2 were assigned to the equatorial protons of the methylene
groups, whereas the low field signals around 4.10–4.20 ppm were assigned to the
axial protons. This NMR data demonstrated that these compounds were in the cone
conformation. Furthermore, this conclusion was supported by 13C NMR data showing
ArCH2Ar resonance signals between 31.0 and 31.4 ppm. The IR spectra revealed that
synthesized compound 9, although bearing proline methyl ester units, showed
characteristic ester peaks around 1744 cm–1, whereas the same peaks were not
observed for synthesized compound 10, bearing proline carboxylic acid units in the
region 1740-1750 cm–1. These data can be used to monitor the proline binding and de-

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1
esterification reaction progress for calixarene compounds 9 and 10. Although the H
NMR spectra of the newly synthesized calixarene compound 9 showed one singlet
peak assigned to the methyl ester protons of proline units around 3.70 ppm, as
expected, the same peak disappeared for carboxylic acid derivative 10 after the
hydrolization of the proline methyl ester of calix[4]arene 9. This data demonstrated
that de-esterification of the proline methyl ester protons of compounds 9 with NaOH
was complete. Furthermore, the new peaks for compounds 9 and 10 seen as singlets
around 1.40 ppm were attributed to the tert-butyl groups of the Boc-protected units;
however, the same peaks were not observed for compound 2. These data are
consistent with the hydrolysis of the Boc-protected units of calixarene compound 10
with TFA and the formation of the final compound 2. In the 13C NMR spectra of these
proline-based calixarenes, it is obvious that compounds 9, 10, and 2 possess certain
symmetry elements, and therefore the number of signals observed in the 13C NMR is
less than the number of C atoms in ligands 9, 10, and 2. Furthermore, all other data
were in agreement with the proposed structures of compounds 9, 10, and 2.
2.2 Optimization of the aldol reactions
Our initial screening efforts focused on the efficiency of compound 2 for
catalyzing the aldol reaction of cyclohexanone (13) with 4-nitrobenzaldehyde (14) in
water at room temperature (Table 1). Compound 2 could efficiently catalyze this aldol
reaction with high conversion values, high diastereoselectivities, and good
enantioselectivities. At the outset, the aldol reaction of cyclohexanone (0.125 mmol)
and 4-nitrobenzaldehyde (2 mmol) was studied by using 10 mol % catalyst 2 in
different amounts of water (Table 1, entries 1-4). The reaction was complete within
24 h in 0.25 mL water at room temperature, and the product was obtained in 99%
conversion, 94/6 dr, and 77% ee (Table 1, entry 4). When the aldol reaction was
performed with 20 mol % catalyst, the product was also obtained in high diastereo-
and good enantioselectivities (70% ee) (Table 1, entry 5). It should be noted that a
decrease in the catalyst loading from 10% to 5% did not significantly affect the
diastereoselectivity or the conversion but did reduce the enantioselectivity (Table 1,
entry 6). Because the highest enantioselectivity was obtained in water with 10 mol %
loading, we also investigated the effect of different additives on the aldol reaction. We
selected readily available acids as additives in the compound 2-catalyzed aldol
reaction. We found that the addition of these acids had no significant effect on the

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enantioselectivity or diastereoselectivity (Table 1, entries 7-10). Under these
conditions, the highest enantiomeric excess was obtained by using 0.25 mL of water.
These initial screening results demonstrated that this new upper rim-functionalized
calix[4]arene-based compound 2 could be used as an effective organocatalyst for an
enantioselective aldol reaction in water.
Table 1 Catalytic aldol reactions between cyclohexanone and 4-nitrobenzaldehydes
catalyzed by 2 in water
O
O
O
OH
Catalyst 2 (10% mol)
H
O2N
Water, r.t., 24h
NO2
2 mmol
0.125 mmol
Entry Water
(mL)
Catalyst:
(% mol)
Additive
Conv.
anti:syna
ee
(%)b
(%)a
90
95
98
99
98
96
77
98
90
99
1
2
1.0
0.50
0.25
0.125
0.25
0.25
0.25
0.25
0.25
0.25
10%
10%
10%
10%
20%
5%
-
91:9
95:5
94:6
94:6
92:8
91:9
93:7
94:6
89:11
94:6
71
75
77
76
70
63
74
75
73
55
-
3
-
4
-
-
5
6
-
7
10%
10%
10%
10%
ClCH2COOH
CH3COOH
PhCOOH
PTSA
8
9
10
a. Determined by 1H NMR spectroscopy of crude mixture.
b. The ee value of anti-isomer was determined by chiral HPLC analysis in comparison with authentic
racemic material.
We further examined the ability of compound 2 to promote the
enantioselective aldol reaction of cyclohexanone and 4-nitrobenzaldehyde in organic
solvents, and the results are summarized in Table 2. When DMF was used as the
solvent, the corresponding aldol product was obtained with high conversion (97%)
after 24 h (Table 2, entry 1). The reaction with DMSO proceeded efficiently and gave
the desired product with good conversion (73%), but the enantioselectivity was low

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(64%) (Table 2, entry 2). CHCl3 and THF were also shown to afford the
corresponding product with good conversions and high enantioselectivities (entries 3
and 4). We also found that the volume of DMF did not have much effect on the
enantioselectivity. Our solvent screening studies clearly demonstrated that compound
2 could efficiently catalyze the asymmetric aldol reaction in polar organic solvents.
Furthermore, different additives had almost no effect on the enantioselectivity of the
reaction (Table 2, entries 7-8).
Table 2 Catalytic aldol reactions between cyclohexanone and 4-nitrobenzaldehyde
catalyzed by compound 2 in organic solvents
O
O
O
OH
Catalyst 2 (10% mol)
H
O2N
Solvent, r.t., 24h
NO2
2 mmol
0.125 mmol
Entry Solvent Amount of
solvent
Additive
Conv.
(%)a
anti:syna
ee
(%)b
1
DMF
0.50
-
97
86:14
84
2
3
4
5
6
7
8
DMSO
CHCl3
THF
0.50
0.50
0.50
0.25
0.125
0.50
0.50
-
73
88
98
87
76
74
67
78:22
87:13
82:18
87:13
85:15
70:30
86:14
64
81
83
80
77
75
84
-
-
DMF
DMF
DMF
DMF
-
-
CH3COOH
PhCOOH
a. Determined by 1H NMR spectroscopy of crude mixture.
b. The ee value of anti-isomer was determined by chiral HPLC analysis in comparison with
authentic racemic material.
2.2 Direct asymmetric aldol reactions catalyzed by compound 2
The scope of this aldol reaction using upper rim-functionalized calix[4]arene-
based compound 2 as a catalyst in the presence of a large amount of water was
studied, and the results are summarized in Table 3 (Method A). The results
demonstrated the catalytic efficiency of compound 2. It catalyzed the aldol reaction of
a variety of substituted aromatic aldehydes, with cyclohexanone affording aldol
products 13a to 13j in moderate to good enantioselectivity and high

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diastereoselectivity. The p-substituted benzaldehydes 12a, 12d, 12g, 12h, 12i, and 12j
afford the aldol product in ee of >75% (Table 3, entries 1, 5, 8, 9, and 10). In contrast,
the reaction with o-substituted benzaldehydes (12c and 12f) and m-substituted
benzaldehydes (12b and 12e) provided lower enantioselectivity than that of p-
substituted donors. In all of the cases, the reactions proceeded smoothly at room
temperature, and diastereoselectivity ranged from good to excellent.
Having established the optimal reaction conditions for the reaction in organic
solvents (Table 2), we then tested the catalytic efficiency of compound 2 in the
enantioselective aldol reaction between cyclohexanone and a variety of substituted
benzaldehydes in DMF (Table 3, Method B). In most cases, the aldol products were
obtained in high yields and with good enantioselectivities. Among these aldehydes,
nitro-substituted benzaldehydes offered the best enantioselectivity, and the desired
aldol products were obtained in good chemical yields with anti- diastereoselectivity.
For example, when o-nitrobenzaldehyde was used, the anti-aldol adduct 13c was
obtained in 90% chemical yield with 92:8 dr and 84% ee. As seen in Table 3, we
observed that the use of DMF has a positive effect on the enantioselectivity but
negative effect on the diastereoselectivity of the rection.
Table 3 Direct aldol reaction between various benzaldehydes and cyclohexanone with
compound 2
O
Catalyst 2
(10% mol)
O
OH
O
R
R
H
Water (0.25 mL)
or DMF (0.5 mL)
r.t.
12
11
13a-j
Aldehyde (R)a
Entry
Yield (%)b
anti:sync
ee (%)d
4-NO2Ph (A)
(B)
3-NO2Ph (A)
(B)
2-NO2Ph (A)
(B)
93
91
70
91
87
90
91
87
94
96
92
94:6
86:14
95:5
87:13
73:27
92:8
61:39
80:20
68:32
60:40
90:10
77
84
70
84
70
84
80
80
74
80
76
1
2
3
4
5
6
4-ClPh (A)
(B)
3-ClPh (A)
(B)
2-ClPh (A)

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(B)
82
86:14
83
4-BrPh (A)
(B)
4-FPh (A)
(B)
4-CNPh (A)
(B)
4-CF3Ph (A)
(B)
93
82
93
91
94
79
94
91
88:12
73:27
60:40
67:33
91:9
85:15
89:11
70:30
76
75
75
73
77
81
77
60
7
8
9
10
a. (A): Method A (in water), (B): Method B (in DMF).
b. Isolated yield after flash column chromatography on silica gel.
c. Determined by 1H NMR spectroscopy of crude mixture.
d. The ee value of anti-isomer was determined by chiral HPLC analysis in comparison with authentic
racemic material.
Together, the abovementioned results led us to suggest a mechanism based on
general enamine catalysis for the compound 2 catalyzed aldol reaction performed in
water. As shown in Fig. 2, we hypothesized that under our reaction conditions, a
hydrophilic region and a hydrophobic region can be created by the formation of
hydrogen bonds between the free OH groups of interfacial water molecules and the
OH and NH groups of the calix[4]arene moiety, which improve the activity of organic
catalysis in water. The transition state of the reaction can be described according to a
Houk-List model.17

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OH
H
N
O
N
H
O
H
H
O
H
O
H
O
O
H
O
O
H2O
H
O
O
N
H
H
H
HO
HN
O
H
O
H
Figure 2. Proposed structure of catalyst 2 in the water
3. Conclusion
In summary, we developed a practical synthesis of compound 2, a novel
organocatalyst containing an L-proline on the upper side of the calix[4]arene
scaffolds, and evaluated its ability to catalyze enantioselective aldol reactions between
substituted benzaldehydes and cyclohexanone. Considering the catalytic inefficiency
of L-proline for the aldol reaction in water, the results presented here clearly
demonstrate the enormous effect of the hydrophobic part of the calix[4]arene of
compound 2 on the reactivity and selectivity in water. We demonstrated that
compound 2 was able to promote enantioselective aldol reactions directly in the
presence of excess amounts of water in high yields (up to >94%) with good
enantioselectivities (up to >80%) and diastereoselectivities (up to 95:5). We also
found that organocatalyst 2 can catalyze direct aldol reactions in DMF with good
diastereoselectivities (up to 92:8) and good enantioselectivities (up to 84%). More
detailed studies on the mechanism and synthetic applications of these L-proline-
functionalized calixarene derivatives in catalytic asymmetric synthesis are currently in

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progress in our laboratory.
4. Experimental
4.1 General
All chemical reagents, starting materials, and solvents were purchased from
Aldrich, Fluka and Merck. Flash column chromatography (FC) was performed by
using glass columns with flash grade silica gel (Merck Silica Gel 60). Reactions were
monitored by thin layer chromatography (TLC) using pre-coated silica gel plates. All
organic extracts were dehydrated over oven dried MgSO4 and concentrated by using
13
rotary evaporator before being subjected to FC. 1H NMR and C NMR spectra were
recorded on Varian 400 MHz spectrometer using CDCl3 as the solvent. Chemical
shifts values are reported in ppm from tetramethylsilane. FTIR spectra were evaluated
on a Perkin Elmer spectrum 100 FTIR spectrometer. Elemental analyses were
performed using a Leco CHNS-932 analyzer. Enantiomeric excess (ee) values of
chiral adducts were detected by a HPLC (Agilent 1200 Series) system using a
Chiralcel OD-H column. Melting points were determined on an EZ-Melt apparatus in
a sealed capillary.
4.2 Synthesis of 5,17-Bis(N-Boc-trans-4-amino-L-proline metyl ester)-11,23-di-
tert-butylcaliks[4]aren (9)
To a stirred solution of 5,17-bis(chloromethyl)-11,23-di-tert-butylcaliks[4]aren (8)
(0.50 g, 0.79 mmol) and triethylamine (0.66 mL, 4.74 mmol) in dry dichloromethane
(20 mL), N-Boc-trans-4-amino-L-proline methyl ester hydrochloride (0.47 g, 1.66
mmol) in dry dichloromethane (10 mL) mixture containing triethylamine (0.23 mL,
1.66 mmol) was added drop wise at room temperature and under N2. The reaction
mixture was allowed to stand overnight at room temperature. After filtration, the
solution was evaporated to dryness. The residue was washed with water and dried
over MgSO4. Then, the product was recrystallized from CH2Cl2 and MeOH to obtain
1
pure compound (9) in 90% yield as a pale yellow solid with mp >300 °C. H NMR
(400 MHz, CDCl3): δ 1.22 (s, 18H, But), 1.40 (s, 18H, OC(CH3)3), 1.82-1.90 (m, 2H,
ProC5), 2.28-2.49 (m, 2H, ProC5), 3.22-3.31 (bm, 6H, ProC4 and ArCH2Ar), 3.49-
3.51 (bm, 4H, ProC5), 3.71 (s, 6H, COOCH3), 3.74-3.75 (m, 4H, CH2NH), 4.17-4.28
(m, 6H, ProC1 and ArCH2Ar), 6.94 ( s, 4H, ArH), 7.05 (s, 4H, ArH). 13C NMR (100
MHz, CDCl3): δ 173.7, 154.3, 153.7, 147.9, 146.8, 133.1, 128.7, 128.5, 127.4, 125.8,
80.1, 67.8, 58.1, 55.1, 52.1, 45.9, 34.1, 32.2, 31.5, 29.7, 28.2. FTIR (ATR)

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(characteristic frequencies): 2952, 2869, 1744, and 1696 cm-1; Anal.Calc. for (%)
C60H80N4O12: C, 68.68; H, 7.68; N, 5.34; Found: C, 68.73; H, 7.61; N, 5.37.
4.3 5,17-Bis(N-Boc-trans-4-amino-L-proline carboxylic acid)-11,23-di-tert-
butylcaliks[4]aren (10)
Compound 9 (0.50 g, 0.48 mmol) was stirred in methanol (10 mL) for 30 min. To this
mixture a 2M NaOH (2.65 mL, 5.31 mmol) solution was added and stirred at room
temperature for 15 hours. Next, 0.5 M hydrochloride acid (40 mL) was added to this
stirred mixture. The aqueous solution was extracted with dichloromethane (2x50 mL)
and ethyl acetate (2x20 mL) respectively. Organic phases were combined and dried
over MgSO4. After evaporating of residue, 0.22 g of pure compound 10 was obtained
1
as a white solid in 44% yield with m.p. >300 °C. H NMR (400 MHz, CDCl3): δ 1.24
(s, 18H, But), 1.40 (s, 18H, OC(CH3)3), 1.80-1.90 (m, 2H, ProC5), 2.30-2.44 (m, 2H,
ProC5), 3.22-3.37 (bm, 6H, ProC4 and ArCH2Ar), 3.50-3.58 (bm, 4H, ProC5), 3.65-
3.73 (m, 4H, CH2NH), 4.17-4.30 (m, 6H, ProC1 and ArCH2Ar), 6.95 ( s, 4H, ArH),
13
7.07 (s, 4H, ArH). C NMR (100 MHz, CDCl3) δ 173.7, 153.7, 148.1, 146.6, 144.4,
127.8, 127.6, 127.2, 126.0, 125.7, 80.1, 67.8, 58.2, 55.1, 45.7, 34.0, 32.5, 31.4, 29.7,
28.2. FTIR (ATR) (characteristic frequencies): 3170, 2957 and 1672 cm-1; Anal.Calc.
for (%) C58H76N4O12: C, 68.21; H, 7.50; N, 5.49; Found: C, 68.19; H, 7.55; N, 5.47.
4.4
5,17-Bis(trans-4-amino-L-proline
carboxylic
acid)-11,23-di-tert-
butylcaliks[4]aren (2)
To a solution of compound 10 (0.50 g, 0.49 mmol) in dry dichloromethane (30 mL),
trifluoroacetic acid (TFA) (1.52 mL) was added and stirred at room temperature
overnight. Then, the solution was evaporated to dryness and the residue was dissolved
in dry dichloromethane (100 mL). Organic phases were extracted with 5% NaHCO3
(2x20 mL). The aqueous phase was extracted by ethyl acetate (2x20 mL). All organic
phases were combined and dried over MgSO4. After evaporating of organic residue,
pure compound was obtained with quantitative yield m.p. >300 °C. 1H NMR (400
MHz, CDCl3): δ 1.21 (s, 18H, But), 2.30-2.50 (m, 2H, ProC5), 3.10-3.19 (m, 2H,
ProC5), 3.20-3.40 (bm, 6H, ProC4 and ArCH2Ar), 3.65-3.98 (bm, 8H, ProC5 and
CH2NH), 4.19-4.42 (m, 6H, ProC1 and ArCH2Ar), 7.05-7.21 (bs, 8H, ArH). 13C NMR
(100 MHz, CDCl3) δ 173.8, 147.9, 146.6, 144.7, 132.6, 128.9, 128.5, 127.4, 125.9,
67.8, 58.0, 55.0, 46.0, 34.1, 32.1, 31.5, 29.7. FTIR (ATR) (characteristic frequencies):
2960, 2849 and 1663 cm-1; Anal.Calc. for (%) C48H60N4O8: C, 70.22; H, 7.37; N,
6.82; Found: C, 70.19; H, 7.44; N, 6.77.

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4.5 General procedure for the enantioselective direct aldol reaction
The following procedure for the reaction of cyclohexanone with 4-nitrobenzaldehyde
in brine is representative.
To a solution of cyclohexanone (2.0 mmol) in water (0.25 mL) was added 4-nitro
benzaldehyde (0.25 mmol) and compound 2 (0.025 mmol). Upon consumption of 4-
nitrobenzaldehyde (monitored by TLC), the reaction mixture was extracted with
EtOAc. Then the organic layers were combined, dried with anhydrous MgSO4,
concentrated to dryness under reduced pressure, and subjected to column
chromatography using 1:3 EtOAc : Hexanes as the eluent to afford the product 13a
purified by preparative TLC.
4.5.1 (S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one (13a).18a,b It was
obtained in a maximum of 93% yield and 77% ee. anti/syn: 94:6, anti-diastereomer;
1H NMR (400 MHz, CDCl3 δ ppm): 1.24-2.02 (m, 6H), 2.28-2.40 (m, 2H), 2.51-2.60
(m, 1H), 4.12 (s, 1H), 4.78 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 8.18 (d, J =
8.4 Hz, 2H). 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: tminor = 26.0 min and
tmajor = 33.2 min.
4.5.2 (S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one (13b).18a It was
obtained in a maximum of 70% yield and 70% ee. anti/syn: 95:5, anti-diastereomer;
1H NMR (400 MHz, CDCl3 δ ppm): 1.34-2.13 (m, 6H), 2.30-2.54 (m, 2H), 2.61-2.63
(m, 1H), 4.12 (s, 1H), 4.84 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.68 (t, J =
7.6 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.26 (d, J = 1.6 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: tmajor = 23.6 min and tminor = 28.8 min.
4.5.3 (S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one (13c).18a It was
obtained in a maximum of 87% yield and 70% ee. anti/syn: 73:27, anti-diastereomer;
1H NMR (400 MHz, CDCl3 δ ppm): 1.48-1.70 (m, 6H), 2.23-2.38 (m, 2H), 2.68-2.70
(m, 1H), 4.02 (s, 1H), 5.43 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.50 (t, J =
7.7 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 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: tmajor = 24.3 min and tminor = 26.1 min.
4.5.4 (S)-2-((R)-Hydroxy(4-chlorophenyl)methyl)cyclohexan-1-one (13d).18c It
was obtained in a maximum of 91% yield and 80% ee. anti/syn: 61:39, anti-
1
diastereomer; H NMR (400 MHz, CDCl3 δ ppm): 1.22-2.10 (m, 6H), 2.33-2.53 (m,

ACCEPTED MANUSCRIPT
2H), 2.55-2.63 (m, 1H), 3.62 (s, 1H), 4.77 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 8.7 Hz, 2H). 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: tminor = 21.9 min and tmajor = 25.8 min.
4.5.5 (S)-2-((R)-Hydroxy(3-chlorophenyl)methyl)cyclohexan-1-one (13e).18d It was
obtained in a maximum of 94% yield and 74% ee. anti/syn: 68:32, anti-diastereomer;
1H NMR (400 MHz, CDCl3 δ ppm): 1.28-2.04 (m, 6H), 2.31-2.40 (m, 3H), 3.94 (s,
1H), 4.80 (d, J = 8.8 Hz, 1H), 7.20-7.25 (m, 3H, Ar), 7.32 (s, 1H, Ar). The optical
purity was determined by HPLC on Chiralpak OD-H column [hexane/2-propanol
96:4, 220 nm, flow rate 1.0 mL/min], anti: tmajor = 23.2 min and tminor = 25.8 min.
4.5.6 (S)-2-((R)-Hydroxy(2-chlorophenyl)methyl)cyclohexan-1-one (13f).18d It
was obtained in a maximum of 92% yield and 76% ee. anti/syn: 90:10, anti-
1
diastereomer; H NMR (400 MHz, CDCl3 δ ppm): 1.52-2.10 (m, 6H), 2.25-2.42 (m,
2H), 2.60-2.68 (m, 1H), 3.89 (s, 1H), 5.30 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz,
1H), 7.24 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.5 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: tminor = 17.0 min and tmajor = 21.9
min.
4.5.7 (S)-2-((R)-Hydroxy(4-bromophenyl)methyl)cyclohexan-1-one (13g).18a,b It
was obtained in a maximum of 93% yield and 76% ee. anti/syn: 88:12, anti-
1
diastereomer; H NMR (400 MHz, CDCl3 δ ppm): 1.20-1.31 (m, 1H), 1.49-1.78 (m,
4H), 2.02-2.10 (m, 1H), 2.28-2.52 (m, 3H), 4.04 (d, J = 2.7 Hz, 1H), 4.71 (dd, J = 8.7,
2.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H). The optical purity was
determined by HPLC on Chiralpak OD-H column [hexane/2- propanol 90:10, 220
nm, flow rate 0.5 mL/min], anti: tminor = 32.9 min and tmajor = 39.3 min.
4.5.8 (S)-2-((R)-Hydroxy(4-fluorophenyl)methyl)cyclohexan-1-one (13h).18c It was
obtained in a maximum of 93% yield and 75% ee. anti/syn: 60:40, anti-diastereomer;
1H NMR (400 MHz, CDCl3 δ ppm): 1.22-1.30 (m, 1H), 1.50-1.78 (m, 4H), 2.01-2.13
(m, 1H), 2.30-2.55 (m, 3H), 4.01 (s, 1H), 4.76 (d, J = 8.8 Hz, 1H), 7.01-7.08 (m, 2H),
7.28-7.33 (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: tminor = 41.6
min and tmajor = 47.1 min.
4.5.9 (S)-2-((R)-Hydroxy(4-cyanophenyl)methyl)cyclohexan-1-one (13i).18d It was
obtained in a maximum of 94% yield and 77% ee. anti/syn: 95:5, anti-diastereomer;

ACCEPTED MANUSCRIPT
1H NMR (400 MHz, CDCl3 δ ppm): 1.30-1.41 (m, 1H), 1.42-1.70 (m, 3H), 1.72-1.86
(m, 1H), 2.02-2.15 (m, 1H), 2.40 (td, J = 12.9, 6.0 Hz, 1H), 2.44–2.62 (m, 2H), 4.12
(d, J = 3.0 Hz, 1H), 4.82 (dd, J = 8.1, 3.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.62 (d, J
= 8.1 Hz, 2H). The optical purity was determined by HPLC on Chiralpak OD-H
column [hexane/2-propanol 95:5, 220 nm, flow rate 1 mL/min], anti: tminor = 54.4 min
and tmajor = 68.4 min.
4.5.10
(S)-2-((R)-Hydroxy(4-trifluoromethhylphenyl)methyl)cyclohexan-1-one
(13j).18d It was obtained in a maximum of 94% yield and 77% ee. anti/syn: 89:11,
1
anti-diastereomer; H NMR (400 MHz, CDCl3 δ ppm): 1.22-1.46 (m, 1H), 1.48-1.80
(m, 4H), 2.05–2.13 (m, 1H), 2.33 (td, J = 12.9, 4.8 Hz, 1H), 2.45-2.55 (m, 1H), 2.68-
2.80 (m, 1H), 4.01 (t, J = 3.0 Hz, 1H), 4.85 (d, J = 8.7 Hz, 1H), 7.42 (t, J = 7.2 Hz,
1H) 7.53–7.75 (m, 3H). The optical purity was determined by HPLC on Chiralpak
OD-H column [hexane/2-propanol 95:5, 220 nm, flow rate 1 mL/min], anti: tminor
=
17.0 min and tmajor= 21.9 min.
Acknowledgements
The financial support the Scientific and Technological Research Council of Turkey
(TUBITAK grant no.112T349 and CMST COST Action CM1005), and the Research
Foundation of Selcuk University (BAP) is gratefully acknowledged.
References
1. Rouhi, M. Chem. Eng. News. 2002, 80, 43.
2. (a) Berkessel, A. and Groger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim, 2005; (b) Dalko, P. I. Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Wiley-VCH: Weinheim, 2007. For general reviews on
asymmetric organocatalysis, see: (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719; (d) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138; (e) Notz, W.;
Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580; (f) List, B. Synlett 2001, 11,
1685; (g) Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431; (h)
Pellissier, H. Adv. Synth. Catal. 2012, 354, 237.
3. (a) Trost, B.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600; (b) Guillena, G. In
Modern Methods in Stereoselective Aldol Reactions, ed. Mahrwald, R. Wiley-VCH:
Weinheim, 2013, p. 155.
4. List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000, 122, 2395.

ACCEPTED MANUSCRIPT
5. For general reviews, see: (a) Mukherjee, S.; Wang, J. W.; Hoffmann S.; List, B.
Chem. Rev. 2007, 107, 5471; (b) Guillena, G.; Najera, C.; Ramon, D. Tetrahedron:
Asymmetry. 2007, 18, 2249.
6. (a) Scheer U.; Mahrwald, R. Chem.-Eur. J. 2013, 19, 14346; (b) Raj, M.; Singh, V.
K. Chem. Commun. 2009, 44, 6687; (c) Gruttadauria, M.; Giacalone, F.; Noto, R.
Adv. Synth. Catal. 2009, 351, 33; (d) Paradowska, J.; Stodulski, M.; Mlynarski, J.
Angew. Chem. Int. Ed. 2009, 48, 4288. (e) Li, C. J. Chem. Rev. 2005, 105, 3095.
7. (a) Pedrosa, R.; Andres, J. M.; Manzano, R.; Roman, D.; Tellez, S. Org. Biomol.
Chem. 2011, 9, 935; (b) Tang, Z.; Yang, Z. H.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.;
Jiang, Y. Z. Org. Lett. 2004, 6, 2285; (c) Nyberg, A. I.; Usano, A.; Pihko, P. M.
Synlett 2004, 11, 1891; (d) Dziedzic, P.; Zou, W.; Ibrahem, I.; Sunden, H.; Cordova,
A. Tetrahedron Lett. 2006, 47, 6657; (e) Gruttadauria, M.; Giacalone, F.; Marculescu,
A. M.; Noto, R. Adv. Synth. Catal. 2008, 350, 1397; (f) Blackmond, D. G.;
Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798 and
references cited therein; (g) Burroughs, L.; Vale, M. E.; Gilks, J. A. R.; Forintos, H.;
Hayes, C. J.; Clarke, P. A. Chem. Commun. 2010, 46, 4776.
8. (a) Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 9, 1090; (b) Peng, Y. Y.;
Ding, Q. P.; Li, Z.; Wang, P. G.; Cheng, J. P. Tetrahedron Lett. 2003, 44, 3871; (c)
Chimni, S. S.; Mahajan, D.; Babu, V. V. S. Tetrahedron Lett. 2005, 46, 5617; (d)
Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem. Commun.
2007, 9, 957.
9. For selected examples, see (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.; Uru-Shima, T.; Shoji, M. Angew. Chem. Int. Ed.
2006, 45, 958.
10. Gutsche, C. D. Calixarenes An introduction 2nd Edition, The Royal Society of
Chemistry, Thomas Graham House, Cambridge, 2008.
11. (a) Vicens, J.; Harrowfield, J.; Backlouti, L. Eds. Calixarenes in the Nanoworld;
Springer, Dordrecht, 2007; (b) Mandolini, L.; Ungaro, R.; Calixarenes in Action;
Imperial College Press; London, 2000; (c) Joseph, R.; Rao, C. P. Chem. Rev. 2011,
111, 4658; (d) Sirit, A.; Yilmaz, M. Turk. J. Chem. 2009, 33, 159 and references
therein.
12. Eymur, S.; Akceylan, E.; Sahin, O.; Uyanik, A.; Yilmaz, M. Tetrahedron 2014,
70, 4471.
13. Xu, Z. X.; Li, G. K.; Chen, C. F.; Huang, Z. T. Tetrahedron 2008, 64, 8668.

ACCEPTED MANUSCRIPT
14. Gutsche, C. D.; Iqbal, M.; Stewart, D. J. Org. Chem. 1986, 51, 742.
15. Dalbavie, J. O.; de Vains, J. B. R.; Lamartine, R.; Lecocq, S.; Perin, M. Eur. J.
Inorg. Chem. 2000, 4, 683.
16. Bayrakcı, M.; Ertul, S.; Yilmaz, M. J. Chem. Eng. Data. 2011, 56, 4473.
17. (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125,
16; (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003,
125, 2475.
18. (a) D’Elia, V.; Zwicknagl, H.; Reise, O. J. Org. Chem. 2008, 73, 3262; (b) Chen,
F.; Huang, S.; Zhang, H.; Liu, F.; Peng, Y. Tetrahedron 2008, 6, 9585; (c) Maya, V.;
Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593; (d) Fu, S. D.; Fu, X. K.; Zhang, S. P.;
Zou, X. C.; Wu, X. J. Tetrahedron: Asymmetry 2009, 20, 2390.