Inherently chiral calix[4]arene-based bifunctional organocatalysts for enantioselective aldol reactions

Article abstract of DOI:10.1016/j.tet.2008.07.001

Two optical pure m-dimethylamino substituted inherently chiral calix[4]arene derivatives 8a and 8b bearing an l-prolinamido group have been synthesized by two routes, and structurally studied by the usual spectroscopic methods and X-ray crystallographic analysis. It was found that both of 8a and 8b could be utilized as bifunctional organocatalysts to efficiently promote the aldol reactions between aromatic aldehydes and ketones in the presence of acetic acid. Especially, with 8a as the catalyst, the reaction between 4-nitrobenzaldehyde and cyclopentanone at -20 °C gave the anti-aldol product up to 94% ee, while the anti-aldol product in up to 94:6 dr and 79% ee was obtained when 4-cyanobenzaldehyde was used as the aldol donor. Moreover, it was also demonstrated that the inherently chiral calixarene skeleton with (cS)-conformation in 8a was identified as the matched configuration of the stereogenic elements, and the inherently chiral moiety might play an important role in helping to stereocontrol the reaction.

Full text of DOI:10.1016/j.tet.2008.07.001

Tetrahedron 64 (2008) 8668–8675
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Inherently chiral calix[4]arene-based bifunctional organocatalysts for
enantioselective aldol reactions
,
,
,
a,
*
Zhen-Xiang Xu a b, Guang-Ke Li a b, Chuan-Feng Chen a , Zhi-Tang Huang
*
a Beijing National Laboratory for Molecular Sciences, Laboratory of Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
b Graduate School, Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2008
Received in revised form 25 June 2008
Accepted 1 July 2008
Available online 3 July 2008
Two optical pure m-dimethylamino substituted inherently chiral calix[4]arene derivatives 8a and 8b
bearing an L-prolinamido group have been synthesized by two routes, and structurally studied by the
usual spectroscopic methods and X-ray crystallographic analysis. It was found that both of 8a and 8b
could be utilized as bifunctional organocatalysts to efficiently promote the aldol reactions between ar-
omatic aldehydes and ketones in the presence of acetic acid. Especially, with 8a as the catalyst, the re-
action between 4-nitrobenzaldehyde and cyclopentanone at ꢀ20 ꢁC gave the anti-aldol product up to
94% ee, while the anti-aldol product in up to 94:6 dr and 79% ee was obtained when 4-cyano-
benzaldehyde was used as the aldol donor. Moreover, it was also demonstrated that the inherently chiral
calixarene skeleton with (cS)-conformation in 8a was identified as the matched configuration of the
stereogenic elements, and the inherently chiral moiety might play an important role in helping to
stereocontrol the reaction.
Keywords:
Inherently chiral calix[4]arene
Organocatalyst
Enantioselective aldol reaction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
functions of Boc-L L-
-proline auxiliary, and also found8 that Boc-
proline could be used as the chiral acylating reagent for kinetic
resolution of the racemic meta-substituted aminocalix[4]arenes.
These approaches allow the convenient gram-scale synthesis of the
optical pure inherently chiral calixarenes, which provides the basis
for the further research on the practical applications of inherently
chiral calixarenes in such as asymmetric catalysis.
Inherently chiral calixarenes1 are a class of representative chiral
macrocyclic compounds whose chiralities originate from the
asymmetric array of achiral subunits on the calixarene skeleton.
Since, Gutsche and No2 reported the first example of inherently
chiral calix[4]arene in 1982, there has been increasing interest in the
synthesis of inherently chiral calixarenes for their unique structures
and potential applications in chiral recognition and asymmetric
catalysis. Consequently, some approaches to synthesis of inherently
chiral calix[4]arenes have been developed during the past two
decades.1 However, there still has been short of effective optical
resolution approaches to optical pure inherently chiral calixarenes,
which thus impeded their practical applications.3 As a result, only
two reports on asymmetric catalysis of inherently chiral calixarenes
with low efficiencies have been hitherto reported.4
In the past decade, a great deal of attention has been devoted to
the possibility of developing enantioselective catalytic processes
with high levels of chemical efficiency and stereocontrol promoted
not by organometallic species but by wholly organic molecules,9
which have shown their synthetic usefulness in enantioselective
C–C as well as heteroatom–C bond formation. In both types of
transformations, proline10 has shown its versatility as catalyst, its
use being especially successful in the enantioselective direct aldol
reaction since the pioneering work by List and co-workers.11 Since
In recent years, we5 and other groups6 have developed an ef-
fective approach to enantiopure inherently chiral calixarene de-
rivatives by introduction of a chiral auxiliary and then separation of
subsequent diastereomers via column chromatography on silica gel,
preparative TLC, or even simple crystallization. More recently, we
reported a more convenient approach7 to the enantiopure meta-
substituted inherently chiral calix[4]arenes based on the dual
then, its several derivatives,12 especially
L
-prolinamides,13 derived
from -proline and different building block amines appearing
L
promising for catalyst design, have been synthesized and applied
for highly enantioselective direct aldol reactions. Promoted by
Najera’s13a,b work that axially chiral 2,20-diamino-1,10-binaph-
thalene-based bifunctional catalysts were recently developed for
the promotion of the enantioselective aldol reaction, we herein
report the synthesis of two enantiopure meta-substituted in-
herently chiral calixarenes bearing proline moiety, and their
applications as novel bifunctional organocatalysts in the enantio-
selective direct aldol reaction.
* Corresponding authors. Tel.: þ86 10 62588936; fax: þ86 10 62554449.
E-mail address: cchen@iccas.ac.cn (C.-F. Chen).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.001

Z.-X. Xu et al. / Tetrahedron 64 (2008) 8668–8675
8669
2. Results and discussion
are depicted in Scheme 1. As shown in route A, starting from the
aminocalix[4]arene 1,14 the racemic inherently chiral calix[4]ar-
ene 2 was easily synthesized by two steps according to the
procedure we reported before.8 Reduction of 2 with Raney Ni
and hydrazine hydrate in THF, and then direct methylation15 of
the reduction product by HCHO and acetic acid in the presence
2.1. Synthesis and structure of organocatalysts
The optical pure inherently chiral calix[4]arene-based orga-
nocatalysts 8a and 8b have been prepared by two routes, which
Route A
O
O
HN
NH2
HN
(1) CH3COCl
Et3N/CH2Cl2
65%
.
NO2
N(CH3)2
1. N2H4 H2O
Raney Ni/THF
NaOtBu
n-BuOH/DMSO
(2) 100% HNO3
AcOH/ CH2Cl2
95%
2. HCHO/NaBH3CN
AcOH/THF
O
O
O
O
O
O
O
O
O
O O
O
95%
80%
2
3
1
O
HN
O
N
N
H
HN
Boc
48%
N(CH3)2
N(CH3)2
CF3CO2H
CH2Cl2
100%
NH2
N(CH3)2
O
O
O
O
O
O O
O
1. Boc-L-proline
DCC/DMAP/DCM
8a
O
O O
O
7a
2. column
O
O
chromatography
N
H
N
NH
NH
4
Boc
(H3C)2N
(H3C)2N
48%
CF3CO2H
CH2Cl2
100%
O
O O
O
O
O O
7b
O
8b
Route B
O
O
N
Boc
HN
N
Boc
NH2
HN
NO2
Boc-L-proline
100% HNO3
DCC/DMAP/DCM
71%
CH2Cl2/AcOH
87%
O
O O
O
O
O
O O
O O
O
O
5
1
6
O
O
N
H
N
HN
HN
Boc
N(CH3)2
N(CH3)2
46%
CF3CO2H
CH2Cl2
100%
O
O
O
O
O
O
O
O
O
8a
.
1. N2H4 H2O/Raney Ni/THF
7a
2. HCHO/NaBH3CN/AcOH/THF
3. column chromatography
O
N
Boc
N
H
NH
NH
(H3C)2N
(H3C)2N
47%
CF3CO2H
CH2Cl2
100%
O
O
O
O
O
O
O
O
7b
Scheme 1. Synthesis of organocatalysts 8a and 8b.
8b

8670
Z.-X. Xu et al. / Tetrahedron 64 (2008) 8668–8675
of NaBH3CN gave compound 3 in 80% total yield. Hydrolysis of
compound 3 with NaOt-Bu in n-butanol and DMSO provided the
O
NO2
N
Boc
NH
1. n-PrI/Na2CO3/CH3CN
2. Raney Ni/N2H4·H2O
3. Boc-L-proline
DCC/DMAP
racemic compound 4 in 95% yield. Condensation of 4 with Boc-
proline in the presence of N,N0-dicyclohexylcarbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP) gave pair of di-
L-
a
astereomers 7a and 7b, which could be resolved by common
silica column chromatography. Diastereomeric pure organo-
catalyst 8a or 8b was finally obtained in a quantitative yield by
hydrolysis of the diastereomers 7a and 7b in dried CH2Cl2 in the
presence of CF3CO2H, respectively. In route B, the optical pure
organocatalysts 8a and 8b were synthesized by introducing Boc-
OH
9
OPr
10
O
N
NH
1. HNO3 (100%)
2. Raney Ni/N2H4·H2O
3. HCHO/NaBH3CN/AcOH
4. CF3CO2H/CH2Cl2
H
N(CH3)2
L-proline as the dual functions of auxiliary according to our
published procedure,7 which showed to be a more convenient
and efficient method than the former one. The structures of 8a
and 8b were characterized by the usual spectroscopic methods
(1H NMR, 13C NMR, and HRMS) and elemental analysis.
Furthermore, we obtained the single crystals of compound
8a by diffusion of n-pentane into the solution of 8a in acetone
and methanol (v/v, 1:1). Based on the X-ray crystallographic
analysis, we designated the absolute configuration of inherently
chiral calixarene moiety in 8a to be cS, in which the dimethyl-
amino group is located at the C-6 position of the calixarene
skeleton (Fig. 1). Thus, the absolute configuration of 8a was
designated to be cS-S. Correspondingly, the absolute configura-
tion of 8b could be designated to be cR-S, in which the dimethyl-
amino group is located at the C-4 position of its calixarene
skeleton.
OPr
11
Scheme 2. Synthesis of compound 11.
2.2. Direct aldol reaction of 4-nitrobenzaldehyde with
cyclohexanone catalyzed by 8a and 8b
With the optical pure calix[4]arene derivatives 8a and 8b in
hand, we then tested their catalytic efficiencies in the enantiose-
lective aldol reaction between 4-nitrobenzaldehyde and cyclohex-
anone. As shown in entries 1 and 2 in Table 1, with 10 mol % of
catalyst 8a or 8b, the direct aldol reaction of 4-nitrobenzaldehyde
and cyclohexanone could be completed within 10 h at room tem-
perature to give the aldol product in a high yield and the anti-iso-
mer in moderate ee value. It has been reported that the
enantioselective direct aldol reaction catalyzed by an organo-
catalyst could be significantly influenced by the acidic additive.16
So, we first tested the aldol reaction catalyzed by 8a or 8b in the
presence of 20 mol % CF3SO3H, and found that a large decrease in
the catalytic activities and the stereoselectivities was observed
(Table 1, entries 3 and 4). Even when we prolonged the reaction
time, low yield of the product and low diastereoselectivity were
only obtained (Table 1, entries 5 and 6). These results might be
attributed to the protonation of the catalyst to lower their nucle-
ophilicity. However, we found that the decrease in the acidity of the
additive could accelerate the aldol reaction (Table 1, entries 7–12).
As a result, the reaction could be completed in 6 h with an obvious
improved enantioselectivity in the presence of 20 mol % AcOH
(Table 1, entries 13 and 14). Moreover, it was also found that de-
creasing the amount of AcOH to 10 mol % could affect the selectivity
but not the yield and the reaction time (Table 1, entries 15 and 16).
These observations suggested that the catalytic system of 10 mol %
of catalyst and 20 mol % of AcOH could be the optimal reaction
conditions.
As comparison, the L-prolinamide derivative 11 was synthe-
sized by the same procedure as described in route B (Scheme 2).
Starting from 4-nitrophenol, compound 10 was synthesized in
three steps in total 95% yield. Nitration of 10 with 100% nitric
acid and then reduction gave the corresponding amine, which
was further methylated by HCHO and acetic acid in the presence
of NaBH3CN, and then followed by deprotection to provide the
target molecule 11 in total 87% yield for the four steps.
The solvent effects on the aldol reaction of 4-nitrobenzaldehyde
and cyclohexanone catalyzed by 8a and 8b were then evaluated,
and the results were shown in Table 2. It was found that the re-
action medium could affect not only the catalytic activities but also
the stereoselectivities of the process. When the reaction was car-
ried out in DMSO, the enantioselectivity could be significantly
improved in the case of both 8a and 8b, but the reaction rate was
very slow (Table 2, entries 1 and 2). Changing the solvent to DMF or
THF, both the reaction rate and the chemical yield were signifi-
cantly increased, while a little decrease in the stereoselectivity was
observed (Table 2, entries 3–6). When the reaction was carried out
in an aqueous solvent, a significant increase in the reaction rate was
found (Table 2, entries 7–12), which is consistent with a recent
report17 that the addition of an amount of water to the solvent
accelerated the reaction rate. Moreover, we also found that the
reaction could be completed in 20 h in pure water (Table 2, entries
Figure 1. (a) Side view and (b) top view of crystal structure of compound 8a. Methanol
molecule and hydrogen atoms are omitted for clarity.

Z.-X. Xu et al. / Tetrahedron 64 (2008) 8668–8675
8671
Table 1
Aldol reaction of 4-nitrobenzaldehyde and cyclohexanone catalyzed by 8a or 8ba
OH
OH
O
O
O
O
10 mol% cat.
additive, r. t.
H
+
+
O2N
O2N
O2N
syn
anti
Entry
Catalyst
Additive
Time (h)
Yieldb (%)
drc (anti/syn)
eed (%, anti)
1
2
3
4
5
6
7
8
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
d
10
10
36
36
76
76
44
44
10
10
20
20
6
98
99
30
Trace
34
26
90
85
98
98
99
99
99
99
99
99
78:22
81:19
29:71
d
44
44
8
d
37
48
13
9
32
23
48
47
58
63
56
40
d
CF3SO3H
CF3SO3H
CF3CO2H
CF3CO2H
Cl2CHCO2H
Cl2CHCO2H
m-NO2–PhCO2H
m-NO2–PhCO2H
PhCO2H
56:44
64:36
80:20
76:24
73:27
71:29
69:31
73:27
73:27
76:24
70:30
75:25
9
10
11
12
13
14
15
16
PhCO2H
CH3CO2H
CH3CO2H
6
6
6
CH3CO2He
CH3CO2He
a
The reactions were conducted with 8a or 8b (10 mol %), additive (20 mol %), aldehyde (0.25 mmol), and ketone (0.2 mL).
Isolated yield.
b
c
Determined by NMR.
d
e
Determined by HPLC; the configuration was assigned as 2R,10S by comparison of retention times.
Acetic acid (10 mol %) was used.
13 and 14), in which a negative effect on the enantioselectivity but
no obvious effect on the diastereoselectivity of the process was
observed (entries 7–14).
In order to improve the enantioselectivity of the process, we
further explored temperature effects on the aldol reaction. As
shown in Table 3, when 8a was used as the catalyst, the
enantioselectivity was increased from 58% (Table 3, entry 1) at
room temperature to 75% at ꢀ20 ꢁC (Table 3, entry 5). However,
with 8b as the catalyst, a little decrease in the enantioselectivity
was observed under the same conditions (Table 3, entries 2, 4,
and 6). Moreover, it was also found that the presence of
10 equiv H2O at low temperature displayed no much better
catalytic efficiency than the ones without water (Table 3, entries
7–10). These observations implied that the stereochemical
pathway of the reaction could be controlled to some extent by
the inherently chiral element of the aminocalix[4]arene moiety,
and catalyst 8a could be the matched diastereomer for this
transformation at low temperature.
Table 2
Solvent effects on the aldol reaction catalyzed by 8a or 8ba
OH
OH
O
O
O
O
10 mol% cat.
20 mol% AcOH
rt, solvent
H
+
+
O2N
O2N
O2N
syn
anti
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
drc (anti/syn)
eed (%, anti)
1
2
3
4
5
6
7
8
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
DMSO
DMSO
DMF
DMF
THF
144
144
44
70
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
80
81
95
95
90
90
99
99
99
99
99
99
99
99
72:28
69:31
65:35
68:32
71:29
61:39
82:18
81:19
83:17
84:16
83:17
84:16
85:15
85:15
72
77
64
69
63
63
64
51
57
46
57
56
49
48
THF
DMSO/H2Oe
DMSO/H2Oe
DMF/H2Oe
DMF/H2Oe
THF/H2Oe
THF/H2Oe
H2Of
9
10
11
12
13
14
20
20
H2Of
a
The reactions were conducted with 8a or 8b (10 mol %), acetic acid (20 mol %), aldehyde (0.25 mmol), and ketone (0.2 mL) in solvent (0.2 mL).
b
c
d
e
f
Isolated yield.
Determined by NMR.
Determined by HPLC; the configuration was assigned as 2R,10S by comparison of retention times.
1:1 (v/v).
10 equiv.

8672
Z.-X. Xu et al. / Tetrahedron 64 (2008) 8668–8675
Table 3
Temperature effects on the aldol reaction catalyzed by 8a or 8ba
OH
O
OH
O
O
O
10 mol% cat.
20 mol% AcOH
H
+
+
O2N
O2N
O2N
syn
anti
Entry
Catalyst
Temperature (ꢁC)
H2O (equiv)
Yieldb (%)
drc (anti/syn)
eed (%, anti)
1
2
3
4
5
6
7
8
9
10
8a
8b
8a
8b
8a
8b
8a
8b
8a
8b
25
25
d
d
d
d
d
d
10
10
10
10
99
99
87
86
75
76
88
87
79
76
73:27
76:24
84:16
78:22
86:14
79:21
86:14
87:13
89:11
85:15
58
63
59
58
75
58
67
55
60
65
ꢀ10
ꢀ10
ꢀ20
ꢀ20
ꢀ10
ꢀ10
ꢀ20
ꢀ20
a
The reactions were conducted with 8a or 8b (10 mol %), acetic acid (20 mol %), aldehyde (0.25 mmol), and ketone (0.2 mL) at the indicated temperature.
b
c
Isolated yield.
Determined by NMR.
d
Determined by HPLC; the configuration was assigned as 2R,10S by comparison of retention times.
As comparison, we further investigated the catalytic efficiency
L-prolinamide derivative 11 in the aldol reaction of 4-nitro-
enantioselectivity than meta-nitrobenzaldehyde with cyclohexa-
none. For 4-cyanobenzaldehyde (Table 5, entry 4), it was found that
not only its yield but the diastereo- (up to 94:6 dr) and enantio-
selectivity (79%) are higher than those of 4-nitrobenzaldehyde with
cyclohexanone. However, low yields and enantioselectivities were
achieved for the direct aldol reactions of biphenyl-4-carbon-
aldehyde and 1-naphthaldehyde with cyclohexanone catalyzed by
8a (Table 5, entries 5 and 6). In the case of aromatic aldehydes
bearing strong electron-rich substituents, no aldol products were
isolated (Table 5, entries 7 and 8). Moreover, the reaction of 4-
nitrobenzaldehyde with other cyclic and acyclic ketones was also
investigated to examine the scope of the aldol donors. Conse-
quently, it was found that acetone and butanone gave the products
in high yields but low enantioselectivities (24% and 57% ee, re-
spectively). However, for cyclopentanone, the diastereoselectivity
is low but a quantitative overall yield and the highest enantiose-
lectivity up to 94% ee were obtained (Table 5, entry 11).
of
benzaldehyde with cyclohexanone under the optimal reaction
conditions described above. As shown in Table 4, when the aldol
reaction proceeded at room temperature, catalyst 11 gave a slight
higher enantioselectivity while a lower reactivity than those of 8a
and 8b (Table 4, entries 1–3). However, compared with the reaction
catalyzed by 11 at ꢀ20 ꢁC, the catalyst 8a gave a significant high
enantioselectivity (75% ee) while 8b showed a low enantiose-
lectivity (Table 4, entries 4–6). These results suggested that the cS-
inherently chiral moiety and the S-stereogenic central moiety in 8a
could be matched to each other in this catalytic process. As a result,
the inherently chiral moiety might play an important role in
helping to stereocontrol the reaction at low temperature.
2.3. Scope and limitations for the aldol reaction
catalyzed by 8a
Under the optimal conditions, a range of aromatic aldehydes
and different ketones including cyclic and acyclic ketones were
further examined to evaluate the generality of 8a in catalyzing di-
rect aldol reactions, and the results were listed in Table 5. As shown
in entries 1–3, the para- and ortho-nitrobenzaldehyde gave better
3. Conclusions
In conclusion, we have synthesized two meta-substituted in-
herently chiral calix[4]arene catalysts 8a and 8b by two routes,
determined their absolute configuration by X-ray crystallographic
Table 4
The aldol reactions promoted by different catalystsa
OH
OH
O
O
O
O
10 mol% 11
20 mol% AcOH
H
+
+
O2N
O2N
O2N
syn
anti
Entry
Catalyst
Temperature (ꢁC)
Time (h)
Yieldb (%)
drc (anti/syn)
eed (%, anti)
1
2
3
4
5
6
11
8a
8b
11
8a
8b
25
25
25
ꢀ20
ꢀ20
ꢀ20
24
6
6
36
36
36
70
99
99
77
75
76
76:24
73:27
76:24
78:22
86:14
79:21
68
58
63
64
75
58
a
The reactions were conducted with the catalyst (10 mol %), acetic acid (20 mol %), aldehyde (0.25 mmol), and ketone (0.2 mL).
b
c
Isolated yield.
Determined by NMR.
d
Determined by HPLC; the configuration was assigned as 2R,10S by comparison of retention times.

Z.-X. Xu et al. / Tetrahedron 64 (2008) 8668–8675
8673
Table 5
Aldol reactions of aromatic aldehydes with different ketones catalyzed by 8aa
O
OH
O
O
OH
10 mol% 8a
20 mol % AcOH
-20 °C
+
ArCHO
+
R1
R1
Ar
R1
Ar
R2
R2
syn
R2
anti
Entry
R1, R2
Ar
Time (h)
Yieldb (%)
drc (anti/syn)
eed (%)
1
2
3
4
5
6
7
8
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
– (CH2)4–
CH3, H
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
4-CNC6H4
Ph–Ph
1-Naphthyl
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
24
24
24
24
48
48
36
36
24
36
15
75
68
65
93
40
86:14
84:16
84:16
94:6
83:17
90:10
d
75 (2R,10S)
76 (2R,10S)
63 (2R,10S)
79 (2R,10S)
56 (2R,10S)
50 (2R,10S)
d
35
de
de
96
d
d
9
10
11
d
24 (R)
57 (R)
94 (2R,10S)
CH3, CH3
–(CH2)3–
80f
100
87:13
56:44
a
The reactions were conducted with 8a (10 mol %), acetic acid (20 mol %), aldehyde (0.25 mmol), and ketone (0.2 mL) at ꢀ20 ꢁC.
b
c
d
e
f
Isolated yield.
Determined by NMR.
Determined by HPLC; the configuration was assigned by comparison of retention times.
No products were isolated.
Linear products (15%).
analysis, and further evaluated their abilities as bifunctional
4.1.1. Synthesis of 3
organocatalysts to catalyze the enantioselective aldol reaction
between aromatic aldehydes and ketones. It was found that both
of the catalysts could promote the aldol reaction between 4-
nitrobenzaldehyde and cyclohexanone in the presence of acetic
acid in high yields and good enantioselectivities. Consequently,
under the optical conditions of 10% of 8a, 20% of acetic acid, and
ꢀ20 ꢁC, the product in 94:6 anti/syn ratio could be obtained
when 4-cyanobenzaldehyde was used as aldol donor, while
a high enantioselectivity up to 94% ee for the anti-isomer was
achieved for the reaction of cyclopentanone with 4-nitro-
benzaldehyde. Moreover, by studies of temperature effect on the
Hydrazine hydrate (4.0 mL) was added dropwise to a suspen-
sion of 2 (1.32 g, 1.53 mmol) and a catalytic amount of Raney Ni
in THF (30 mL). After the mixture was refluxed 2 h under argon,
the Raney Ni was filtered over Hyfro and the solvent was
evaporated. The residue was taken up in CH2Cl2 (50 mL), washed
with H2O (30 mL) and brine (30 mL), and dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was
obtained and used without further purification. A mixture of the
residue and aqueous formaldehyde (37%, 1.34 mL) in THF (28 mL)
was stirred for 15 min. Then NaBH3CN (597 mg, 9.50 mmol) was
added and stirred for another 15 min, following by adding AcOH
(1.79 mL). The resulting solution was stirred for 7 h at room
temperature, 1 N NaOH aqueous solution was then added to
adjust the solution pHz7. The reaction mixture was extracted by
CH2Cl2 (3ꢂ50 mL) and the combined organic phases were
washed with saturated brine and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure, and the crude
product was purified by column chromatography with petroleum
ether/ethyl acetate (10:1, v/v) as an eluent to afford 3 (1.05 g,
80%) as a white solid. Mp: 107–109 ꢁC. 1H NMR (300 MHz,
aldol reaction and comparison with L-prolinamide derivative 11
as the catalyst, we also found that the inherently chiral calix-
arene skeleton with (cS)-conformation in 8a was identified as
the matched configuration of the stereogenic elements, and the
inherently chiral moiety might play an important role in helping
to stereocontrol the reaction. The results we presented here
provided a practical example for asymmetric catalysis of in-
herently chiral calixarene derivatives with high efficiencies. More
applications of the inherently chiral calixarenes in catalytic
asymmetric synthesis are currently under investigation in our
group.
CDCl3):
d 7.76 (s, 1H), 6.83–6.51 (m, 6H), 4.46–4.42 (m, 2H), 4.36
(d, J¼12.8 Hz, 1H), 4.24 (d, J¼13.2 Hz, 1H), 3.99–3.67 (m, 8H), 3.39
(d, J¼13.3 Hz, 1H), 3.16–3.12 (m, 3H), 2.84 (s, 3H), 2.52 (s, 3H),
2.10 (s, 3H), 2.05–1.78 (m, 8H), 1.26–0.73 (m, 39H). MALDI-TOF
MS: m/z 861.2 (Mþ), 884.2 ([MþNa]þ), 900.2 ([MþK]þ). Anal.
Calcd for C56H80O5N2: C, 78.10; H, 9.36; N, 3.25. Found: C, 77.75;
H, 9.43; N, 3.15.
4. Experimental
4.1. General
Melting points were measured with an X-4 digital indicating
melting point apparatus. 1H and 13C NMR spectra were recorded
using a Bruker Spectrospin AV300 instrument. Tetramethylsilane
(TMS) was used as an internal standard, with chemical shifts
expressed in parts per million (ppm) downfield from the standard.
Mass spectra were determined by MALDI-TOF technique. Elemen-
tary analysis was performed in the Analytic Laboratory of this In-
stitute. Flash column chromatography was carried out with silica
gel (160–200 mesh). Other reagents and solvents were purchased
from common commercial sources and were used as received or
purified by distillation from appropriate drying agents.
4.1.2. Synthesis of racemic 4
To a solution of NaOt-Bu (731 mg, 7.62 mmol) in n-BuOH
(65 mL)/DMSO (3.80 mL) was added 3 (328 mg, 0.38 mmol), and
the reaction mixture was refluxed for about 48 h. After removal of
the solvent under reduced pressure, 10% HCl (30 mL) was added,
and the mixture was then extracted with CH2Cl2 (3ꢂ30 mL). The
combined organic phase was washed with H2O and dried over
anhydrous Na2SO4 and concentrated. The residue was separated by
column chromatography (silica gel; petroleum ether/CH2Cl2, 2:1) to
give compound 4 as a white solid (297 mg, 95%). Mp: 96–98 ꢁC. 1H
NMR (300 MHz, CDCl3):
d 6.90 (s, 1H), 6.82–6.79 (m, 3H), 6.65 (s,

8674
Z.-X. Xu et al. / Tetrahedron 64 (2008) 8668–8675
1H), 6.51 (s, 1H), 6.04 (s, 1H), 4.48–4.43 (m, 2H), 4.35 (d, J¼12.6 Hz,
1H), 4.15 (d, J¼12.7 Hz, 1H), 4.04–3.65 (m, 8H), 3.40 (d, J¼12.7 Hz,
1H), 3.16–3.10 (m, 2H), 2.98 (d, J¼12.7 Hz, 1H), 2.79 (s, 3H), 2.26 (s,
3H), 2.01–1.89 (m, 8H), 1.19 (s, 9H), 1.14 (s, 9H), 1.05–0.86 (m, 21H).
(4.07 g, 38.39 mmol) was refluxed for 6 h under nitrogen atmo-
sphere. After removal of the solvent under reduced pressure, 10%
HCl (100 mL) was added, and the mixture was then extracted with
CH2Cl2 (3ꢂ40 mL). The combined organic phase was washed with
H2O and dried over anhydrous Na2SO4 and concentrated to obtain
the etherified product, which was reduced by hydrazine hydrate in
the presence of a catalytic amount of Raney Ni, and then acetylated
13C NMR (75 MHz, CDCl3):
d 154.4, 154.3, 153.8, 149.9, 144.1, 144.0,
143.1, 139.9, 135.4, 134.4, 134.1, 134.0, 133.8, 133.5, 132.0, 126.3,
125.5, 125.1, 124.9, 123.9, 115.8, 77.1, 77.0, 76.2, 42.8, 42.6, 33.93,
33.90, 33.7, 31.7, 31.6, 31.3, 30.7, 28.3, 23.5, 23.4, 23.1, 22.6,10.6, 10.5,
10.3, 10.1. MALDI-TOF MS: m/z 819.1 (Mþ), 842.1 ([MþNa]þ), 858.1
([MþK]þ). Anal. Calcd for C54H78O4N2: C, 79.17; H, 9.60; N, 3.42.
Found: C, 78.93; H, 9.61; N, 3.32.
by L-Boc-proline in the presence of DCC and DMAP to give the
compound 10 in total 95% yield for three steps. Starting from 10, the
prolinamido-derivative 11 as a colorless liquid was obtained in total
87% yield for four steps according to the same procedure as de-
scribed in route B for synthesis of 8a and 8b.
4.1.3. Synthesis of 7a
Compound 10. Mp: 136–138 ꢁC; 1H NMR (300 MHz, CDCl3):
To a solution of racemic 4 (297 mg, 0.36 mmol) in dried CH2Cl2
d
9.29 (br s, 1H), 7.40 (d, J¼8.9 Hz, 2H), 6.83 (d, J¼7.7 Hz, 2H), 4.45
(30 mL) were added
L-Boc-proline (82 mg, 0.38 mmol), DCC
(br s, 1H), 3.88 (t, J¼6.6 Hz, 2H), 3.60–3.20 (m, 2H), 2.51 (br s, 1H),
2.01–1.71 (m, 5H), 1.49 (s, 9H), 1.02 (t, J¼7.4 Hz, 3H). MS (ESI): m/z
348.08 [M]þ. Anal. Calcd for C19H28O4N2: C, 65.49; H, 8.10; N, 8.04.
Found: C, 64.45; H, 8.04; N, 7.81.
(112 mg, 0.54 mmol), and DMAP (22 mg, 0.18 mmol), respectively.
The mixture was stirred at room temperature for 10 h, and the
insoluble DCU formed was then removed by filtration. The filtrate
was concentrated, and the residue was purified by column chro-
matography with petroleum ether/ethyl acetate (15:1 v/v) as an
eluent to afford compounds 7a (178 mg, 48%) and 7b (176 mg, 48%)
both as a white solid. Mp: 90–92 ꢁC; 1H NMR (300 MHz, CDCl3):
Compound 11. 1H NMR (300 MHz, CDCl3):
d 10.10 (s, 1H), 8.26 (d,
J¼2.5 Hz, 1H), 6.68 (d, J¼2.5 Hz, 1H), 6.60 (dd, J¼8.9, 2.5 Hz, 1H),
3.92–3.84 (m, 4H), 3.12–2.95 (m, 2H), 2.65 (s, 6H), 2.26–2.00 (m,
2H), 1.84–1.72 (m, 4H), 1.03 (t, J¼7.4 Hz, 3H). 13C NMR (75 MHz,
d
8.38 (br s, 0.5H), 7.82 (br s, 0.5H), 7.25 (s, 1H), 6.91–6.50 (m, 6H),
CDCl3): d 172.8, 155.5, 144.9, 125.9, 120.4, 108.2, 106.9, 69.65, 61.4,
4.46–4.15 (m, 5H), 4.00–3.65 (m, 8H), 3.65–3.35 (m, 3H), 3.20–3.08
(m, 3H), 2.80 (s, 3H), 2.60–1.85 (m, 5H), 1.85–1.72 (m, 10H), 1.55–
0.83 (m, 48H). MALDI-TOF MS: m/z 1016.3 (Mþ), 1039.3 ([MþNa]þ),
1045.3 ([MþK]þ). Anal. Calcd for C64H93O7N3: C, 75.63; H, 9.22; N,
4.13. Found: C, 76.05; H, 9.47; N, 4.07.
47.4, 44.1, 30.9, 26.3, 22.6, 10.5. HRMS calcd for C16H25N3O2: [M]þ
291.3886, found: 291.2013.
4.2. Crystal data for 8a
C60.5H92N3O7, M¼973.37, trigonal, space group P3221,
¼90.00ꢁ,
4.1.4. Synthesis of 8a
a¼12.9528(18),
b¼12.9528(18),
c¼59.907(12) Å,
a
A solution of 7a (360 mg, 0.35 mmol) and TFA (0.54 mL) in dried
CH2Cl2 (20 mL) were stirred under nitrogen atmosphere at room
temperature for 15 h. After removal of the solvent under reduced
pressure, the residue was taken up in CH2Cl2 (50 mL), washed with
5% NaHCO3 (2ꢂ30 mL), and dried over anhydrous Na2SO4. After
evaporation of the solvent, 8a (320 mg) was obtained in a quanti-
tative yield as a white solid, which was used without further pu-
b
¼90.00ꢁ,
g
¼120.00ꢁ, V¼8704.3(5) Å3, Z¼6, rcalcd¼1.114 cmꢀ3, Mo
Ka
radiation,
l
¼0.71073 Å,
m
¼0.072 mmꢀ1
,
T¼113(2) K,
Rint¼0.0637, R1¼0.0642 (I>2
s(I)). Crystallographic data for the
structure have been deposited with Cambridge Crystallographic
Database as supplementary publication number CCDC 686801.
4.3. A general procedure for aldol reactions
rification. Mp: 130–132 ꢁC; 1H NMR (300 MHz, CDCl3):
d 9.56 (s,
1H), 7.64 (s, 1H), 6.94 (s, 1H), 6.90 (s, 1H), 6.82 (m, 2H), 6.62 (s, 1H),
6.46 (s, 1H), 4.47–4.37 (m, 3H), 4.20 (d, J¼12.8 Hz, 1H), 4.02–3.63
(m, 10H), 3.40 (d, J¼12.8 Hz, 1H), 3.20–2.90 (m, 5H), 2.75 (s, 3H),
To a stirred solution of 10 mol % catalyst in ketones (0.2 mL) at
a given temperature after 15 min, the aldehyde (0.25 mmol) was
added. The mixture was allowed to stir for a given time, then the
solvent was evaporated and the crude product analyzed. If neces-
sary, the crude products were purified by flash chromatography
with hexane/ethyl acetate mixture as eluents.
2.26–1.60 (m, 14H), 1.20 (s, 9H), 1.16 (s, 9H), 1.06–0.76 (m, 21H). 13
C
NMR (75 MHz, CDCl3): d 172.1, 154.3, 153.7, 153.3, 144.4, 143.9, 143.1,
138.6, 134.4, 134.2, 133.9, 133.6, 133.5, 132.1, 131.7, 126.2, 125.6,
125.5, 125.3, 125.1, 123.6, 120.3, 77.2, 76.9, 76.1, 61.1, 47.2, 43.0, 42.7,
33.94, 33.86, 33.6, 31.7, 31.6, 31.2, 31.1, 30.84, 30.75, 26.2, 23.45,
23.38, 23.1, 22.5, 10.6, 10.4, 10.3, 10.0. HRMS calcd for C59H85N3O5:
[M]þ 916.3233, found: 916.6546.
Acknowledgements
We thank the National Natural Science Foundation of China
(20625206), National Basic Research Program (2007CB808004,
2008CB617501) and the Chinese Academy of Sciences for financial
support. We also thank Dr. H.B. Song at Nankai University for de-
termining the crystal structure.
4.1.5. Synthesis of 8b
According to the above method for synthesis of 8a, hydrolyzing
7b (275 mg, 0.27 mmol) gave 8b as a white solid (247 mg). Mp: 128–
130 ꢁC. 1H NMR (300 MHz, CDCl3):
d 9.40 (s, 1H), 7.53 (s, 1H), 7.02 (s,
1H), 6.97 (s,1H), 6.89 (m, 2H), 6.57 (s,1H), 6.37 (s,1H), 4.47–4.38 (m,
3H), 4.21 (d, J¼12.7 Hz, 1H), 4.10–3.58 (m, 10H), 3.37 (d, J¼12.8 Hz,
1H), 3.23–2.85 (m, 5H), 2.76 (s, 3H), 2.22–1.64 (m, 14H), 1.25 (s, 9H),
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