Water promoted enantioselective aldol Reaction by proline-cholesterol and -diosgenin based amphiphilic organocatalysts

Article abstract of DOI:10.1016/j.tet.2013.04.078

A series of proline-cholesterol and -diosgenin based amphiphilic organocatalysts were developed for the first time, and their catalytic activities for the enantioselective aldol reaction were investigated. The results indicated that water can significantl

Full text of DOI:10.1016/j.tet.2013.04.078

Tetrahedron 69 (2013) 5136e5143
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Water promoted enantioselective aldol Reaction by proline-
cholesterol and -diosgenin based amphiphilic organocatalysts
,
a
b
a
a
a,
*
Ting He a, Kun Li a , Ming-Yu Wu , Ming-Bo Wu , Na Wang , Lin Pu , Xiao-Qi Yu
*
a Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064,
People’s Republic of China
b State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of proline-cholesterol and -diosgenin based amphiphilic organocatalysts were developed for the
first time, and their catalytic activities for the enantioselective aldol reaction were investigated. The
results indicated that water can significantly enhance the activity and stereoselectivity of the trans-
formation via micelle formation. TEM and AFM analysis demonstrated that the diameter of the micelle
particles ranged from 200 to 800 nm.
Received 15 January 2013
Received in revised form 9 April 2013
Accepted 17 April 2013
Available online 20 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Proline
Cholesterol
Diosgenin
Aldol reaction
1. Introduction
structural and functional characteristics, organic chemists have
reported some examples describing the asymmetric aldol reaction
Water can play an important role in organic synthesis; in some
cases, it is known that water will accelerate or initiate a reaction.1
For example, Breslow and co-workers reported an ‘in water’ pro-
cedure in which water-accelerated an intermolecular DielseAlder
cycloaddition,2a while Sharpless and co-workers reported several
reaction rate accelerations with ‘on water’ conditions.2b Reactions
using water as solvent have attracted more and more attention
from a synthetic point view because it is environmentally friendly
and safe.3 In the past few years, many publications report the use of
water in organic reactions, but there are only a few examples of
water-accelerated reactions with both high yields and enantiose-
lectivities.4 Even with these limited examples, the specific role of
water in the reactions and how it influences yield and stereo-
selectivity remains unclear.5 Thus, it is necessary to identify specific
transformations that allow for the gathering of evidence to un-
derstand the mechanistic role water.
‘in the presence of water’. After the outstanding discovery by List
and co-workers of the proline-mediated asymmetric aldol reaction,
which proceeds in a polar organic solvent,8 many papers con-
cerning similar asymmetric aldol reactions have appeared.9 How-
ever, only a few conditions demonstrate results comparable with
enzyme due to the poor solubilities of reactants and catalysts. The
use of additives or surfactants has been utilized in an attempt to
solve this problem.9s,10 An alternative solution involves the de-
velopment of amphiphilic catalysts capable of efficiently dispersing
in a biphasic system.11 Toward this end, Hayashi and co-workers
reported on a series of proline-surfactant conjugates as organo-
catalysts for asymmetric aldol reactions (Scheme 1).11a Although
several amphiphilic catalysts have been reported in the past years,
many of them are restricted to incorporating linear alkyl chains as
lipophilic group.11c,d Despite the essential structural roles that
cholesterol and diosgenin play in mammalian cellular membranes
and their improved lipophilic characteristics over linear alkyl
chains, it is surprising that no proline-cholesterol or -diosgenin
amphiphilic catalysts or related reagents have been reported to
date.12
The aldol reaction is a synthetically important reaction for car-
bonecarbon bond formation.6 In nature, enzymes can catalyze the
asymmetric aldol reaction using a hydrophobic pocket (reactive
center) within a water medium.7 In attempts to simulate such
In this work, we first present a series of proline-cholesterol and -
diosgenin conjugates, which can serve as amphiphilic catalysts for
highly stereoselective direct aldol reactions between hydrophobic
reagents. More interestingly, it was discovered that the use of water
* Corresponding authors. E-mail addresses: kli@scu.edu.cn (K. Li), xqyu@scu.e-
du.cn (X.-Q. Yu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.078

T. He et al. / Tetrahedron 69 (2013) 5136e5143
5137
Table 1
Screening of organocatalystsa
Entry
Catalyst
Yieldb (%)
eec (%)
anti/sync
1
2
3
4
5
6
7
8
1a
1b
2a
2b
3a
3b
4a
4b
89
94
96
92
97
93
91
81
67
72
76
75
69
68
69
68
77:23
74:26
78:22
75:25
75:25
75:25
77:23
80:20
Scheme 1. The structures of the amphiphilic catalysts reported in the literature
(TBS¼tert-butyldimethylsilyl; TIPS¼triisopropylsilyl; TBDPS¼tert-butyldiphenylsilyl).
as a reaction medium results in both micelle formation and an
improvement in the yields and stereoselectivities of these orga-
nocatalyzed aldol reactions.
a
The reactions were performed with p-nitrobenzaldehyde (0.2 mmol), cyclo-
hexanone (4 mmol), and catalyst (0.04 mmol) in toluene (0.5 mL) at room tem-
perature for 6 h.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
2. Results and discussion
Table 2
Our newly developed catalysts bear a proline as a mildly hy-
drophilic head group linked to a lipophilic cholesterol or diosgenin
tail via a 5e8 atom carbamate linker. Eight catalysts were suc-
cessfully synthesized and characterized by NMR and HRMS
(Scheme 2).
Organocatalyst catalyzed direct aldol reactions in different organic solvents and
temperaturesa
Entry
Catalysts
Temp
(ꢁC)
Solvent
Yieldb
(%)
eec
(%)
anti/sync
Time
(h)
1
2
3
4
5
2a
2a
2a
2a
2a
rt
rt
rt
rt
rt
Hexane
CHCl3
CH3CN
AcOEt
Isopropyl
ether
THF
MeOH
DMSO
DMF
H2O
Neat
Neat
Neat
Neat
Neat
Neat
Neat
99.0
32.3
43.4
48.6
91.6
66
49
16
62
73
79:21
85:15
82:18
80:20
80:20
6
6
6
6
6
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2b
3b
4a
4b
1b
2a
2b
3b
rt
rt
rt
rt
rt
rt
0
0
0
0
0
ꢀ20
ꢀ20
ꢀ20
ꢀ20
60.0
29.3
34.1
38.8
94.8
99.9
99.0
99.8
>99
73.7
74.5
>99
99.4
96.8
>99
73
48
64
56
42
72
84
85
84
54
72
91
87
84
86
81:19
83:17
65:35
71:29
68:32
95:5
93:7
93:7
93:7
90:10
88:12
93:7
95:5
94:6
6
6
6
6
6
5
6
6
6
6
6
24
24
24
24
10
11
12
13
14
15
16
17
18
19
20
Scheme 2. The structures of the amphiphilic catalysts.
Neat
Neat
Neat
96:4
Our initial screening efforts involved the aldol reaction between
p-nitrobenzaldehyde and cyclohexanone with various catalysts in
the presence of toluene at room temperature. As shown in Table 1,
all of the catalysts exhibited similar catalytic efficiencies, with ex-
cellent yields, but moderate diastereo- and enantioselectivities.
In order to improve the stereoselectivity of the reaction, we
investigated the effects of solvent and temperature under other-
wise similar reaction conditions. A relatively wide range of yields
and stereoselectivities, from low to excellent, were observed, as
summarized in Table 2. The common organic solvents chloroform,
acetonitrile, ethyl acetate, methanol, DMF, and DMSO all provided
low yields and enantioselectivities (entries 2e4 and 7e9). The re-
activity was significantly improved when either hexanes or water
was used as solvent, but the corresponding stereoselectivities were
lower (entries 1 and 10). Good enantioselectivities were observed
when the reaction carried out in the ethereal solvents isopropyl
ether and tetrahydrofuran, but no significant improvement in
chemical yield was obtained. Under neat reaction conditions (cy-
clohexanone as ‘solvent’), the anti-aldol product was obtained al-
most exclusively in 99% yield and 72% ee (entry 11). Subsequently,
a
The reactions were performed with p-nitrobenzaldehyde (0.2 mmol), cyclo-
hexanone (4 mmol), and catalyst (0.02 mmol) in organic solvent (0.5 mL).
b
Isolated yield.
Determined by chiral HPLC analysis.
c
the aldol reaction was carried out neat at lower temperatures to
improve the observed stereoselectivity. Reduction of reaction
temperature did afford higher stereoselectivities, although longer
reaction times were required. Close analysis of the data strongly
suggests that the presence of the catalyst 1b at ꢀ20 ꢁC is most
suitable combination for the asymmetric aldol reactions (entry 17).
We hypothesized that the presence of an additional proton may
help the reaction establish a hydrogen bond between the substrates
and the catalyst. This, in turn, may increase the resulting stereo-
selectivities for the reactions. To explore this hypothesis, we first
examined the reactions with various catalyst loadings (Table 3,
entries 1e5). Both the enantioselectivity and the diaster-
eoselectivity were improved slightly upon lowering the catalyst
loading from 20 to 5 mol % (entries 1e4), but further reduction in

5138
T. He et al. / Tetrahedron 69 (2013) 5136e5143
Table 3
excellent yields and high stereoselectivities (entries 6e10). The
reaction conditions were also suitable for the substituted hetero-
cyclic aldehydes such as nicotinaldehyde and isonicotinaldehyde
(entries 12 and 13, respectively). However, the results were less
satisfactory in the case of benzaldehyde, 4-methoxybenzaldehyde,
and 4-methylbenzaldehyde (entries 11, 14, and 15). For comparison,
the results obtained under neat reaction conditions (no water) are
also listed (Table 5, in parentheses). Overall, the addition of water
significantly improved the observed yield and stereoselectivity of
the reactions, especially for halogenated aromatic aldehydes (en-
tries 6, 7, and 9). Even for aromatic aldehydes bearing electron-
donating groups (entries 14 and 15), the addition of water still
resulted in an improvement in the yield and/or stereoselectivity.
Moreover, the addition of water allowed for reduced reaction
times; the reactions reach completion within 48 h for most alde-
hydes. We also examined organocatalyzed aldol coupling between
cyclopentanone and various aromatic aldehydes under similar re-
action conditions (Table 6). The desired aldol products were ob-
tained in excellent yields, but the diastereoselectivities were not
good. We reason that this is due to a decrease in steric hindrance
and rigidity with the cyclopentanone ring. In contrast to observa-
tions with cyclohexanone, the major stereoisomeric products ob-
tained with cyclopentanone were characterized as the syn isomers,
which were typically obtained with high enantioselectivity. Si-
multaneously, we were pleased to observe an improvement in the
reactivity with of the electron-rich aldehydes such as anisaldehyde
and p-methyl benzaldehyde, which achieved 45 and 91% isolated
yields, respectively (entries 14 and 15). The furaldehyde and thio-
phen-3-carbaldehyde were also suitable electrophiles with cyclo-
pentanone under the same reaction conditions (entries 16 and 17).
It should be noted that, after addition of the catalyst 1b and water,
micelle formation ensued upon vortexing or violent stirring (Fig. 1);
this observation is strong support for the amphiphilic character of
the catalyst.
Organocatalyst catalyzed direct aldol reactions with different catalyst loadings and
additivesa
Entry
Additive
1b (mol %)
Yieldb (%)
eec (%)
anti/sync
1
2
3
4
None
None
None
None
None
TFA
20
15
10
5
1
5
5
5
5
5
99
99
99
99
51.6
Trace
Trace
87
92
99
91
87
87
93
85
d
93:7
95:5
95:5
94:6
93:7
d
5
6d
7
TFA/H2Oe
AcOH
AcOH/H2O
H2Of
d
d
8
9
10
94
93
94
95:5
96:4
96:4
a
The reactions were performed with p-nitrobenzaldehyde (0.2 mmol), cyclo-
hexanone (0.5 mL), and catalyst at ꢀ20 ꢁC for 24 h.
b
Isolated yield.
Determined by chiral HPLC analysis.
The reactions were performed with p-nitrobenzaldehyde (0.2 mmol), cyclo-
c
d
hexanone (1 mL), acid (0.02 mmol), and catalyst (0.01 mmol) at ꢀ20 ꢁC for 24 h.
e
H2O (20
H2O (100
m
m
L).
L).
f
catalyst loading resulted in a stark decrease in yield and stereo-
selectivity (entry 5). Next, we investigated the impact made by
acidic additives to the reaction using 5 mol % catalyst loading
(entries 6e9). Surprisingly, addition of trifluoroacetic acid (TFA,
0.1 equiv) to the reaction drastically inhibited the reaction, result-
ing in only trace product formation (entry 6). The same result was
observed with a combination of water and TFA (entry 7). Addition
of acetic acid (AcOH, 0.1 equiv) provided results comparable to
reaction conditions lacking any additive, though slightly higher
stereoselectivities were observed (entry 8). Unexpectedly, when
a small amount of water was added to the reaction, both the yield
and the stereoselectivity were increased relative to reaction con-
ditions lacking any additive (entry 10). This result suggested that
water might play an important role in the direct aldol reactions
mediated by catalyst 1b. To confirm this idea, the influence of water
content on the aldol reaction was investigated. Excellent yields and
good to high stereoselectivities were obtained with different water
contents (Table 4). Increasing the water content induced a slight
improvement in the stereoselectivities. The presence of the catalyst
1b with 10% water and no other solvent proved to be the best
conditions for the direct aldol reaction (Table 4 entry 4); the anti-
diastereomer was obtained in excellent chemical yield (99%) and
high stereoselectivity (94% ee and 96:4 dr).
To further understand the mechanistic role of water, analysis of
the reaction mixture by TEM and AFM was used to confirm the
existence of micelles. As shown in Fig. 2 and 3, the diameter of
colloidal particles that formed after vortexing the catalyst and re-
agents with water ranged from 200 to 800 nm; only a film was
found in the absence of water (Fig. 2).
These results demonstrate that the amphiphilic catalyst can
assemble themselves into emulsions (W/O), and enhance the re-
activity and stereoselectivity of the direct aldol reaction. Based on
previous reports, the hydrogen bonding enhanced by water be-
tween the substrate and catalyst at the transition state should be
responsible for the observations. The pyrrolidine-based organo-
catalyzed aldol reactions are presumed to proceed via an enamine
intermediate. The water in the emulsion could activate the alde-
hyde for nucleophilic attack by transferring a proton and acceler-
ating the hydrolysis of the imine, resulting in expulsion of the
product and regeneration of the catalyst for the next cycle. Mean-
while, the free OH groups on the surface of the water could link the
proline moiety through hydrogen bonds. These three combined
effects could account for the improvement in the reactivity activity
and diastereoselectivity observed upon vortexing in water.9o,13
Table 4
The influence of the watera
Entry
Waterd (%)
Yieldb (%)
eec (%)
anti/sync
1
2
3
4
5
6
7
8
2
4
5
10
15
20
40
100
98
99
99
99
99
99
98
97
90
91
90
94
91
89
89
91
95:5
96:4
97:3
96:4
96:4
95:5
96:4
96:4
a
The reactions were performed with p-nitrobenzaldehyde (0.2 mmol), cyclo-
hexanone (0.5 mL), catalyst 1b (0.01 mmol), and water at ꢀ20 ꢁC for 24 h.
b
Isolated yield.
Determined by chiral HPLC analysis.
Volume ratio.
3. Conclusions
c
d
In conclusion, proline-cholesterol and -diosgenin based am-
phiphilic organocatalysts were developed for the first time, and
were successfully applied in the direct aldol reaction between cyclic
ketones and aromatic aldehydes. The presence of water with these
organocatalysts leads to micelle formation and a significant en-
hancement in reactivity and stereoselectivity. This kind of amphi-
philic organocatalysts holds promise as a new and efficient
approach for asymmetric synthesis.
Next, the generality of the reaction conditions was examined by
employing various aromatic aldehydes (Table 5). The reaction be-
tween cyclohexanone and aromatic aldehydes bearing strongly
electron-withdrawing groups offered the corresponding anti-aldol
products in both high yield and stereoselectivity (entries 1e5).
Mono- or dihalogenated aromatic aldehydes also provided good to

T. He et al. / Tetrahedron 69 (2013) 5136e5143
5139
Table 5
Direct aldol reactions between aromatic aldehydes and cyclohexanone promoted by organocatalyst 1ba
Entry
1
R
Product
Time (d)
2 (4)
Yieldb (%)
99 (99)
eec (%)
96 (94)
anti/synd
o-NO2eC6H4
96:4 (94:6)
2
3
m-NO2eC6H4
1
1
97
99
94
93
98:2
97:3
p-NO2eC6H4
4
5
p-CNeC6H4
p-CF3eC6H4
2 (4)
99 (94)
91 (94)
97:3 (86:14)
97:3
2
99
93
6
p-CleC6H4
p-BreC6H4
o-BreC6H4
p-FeC6H4
2 (4)
2 (4)
2
93 (78)
89 (24)
97
93 (84)
98 (82)
95
97:3 (97:3)
98:2 (55:45)
>99:1
7
8
9
2 (4)
62 (41)
94 (81)
96:4 (93:7)
99:1
10
2,6-CleC6H3
1
99
96
11
Ph
4 (4)
47 (33)
92 (79)
97:3 (95:5)
12
13
3-Pyridinyl
4-Pyridinyl
1 (4)
99 (71)
92 (84)
92:8 (91:9)
96:4
1
95
92
(continued on next page)

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T. He et al. / Tetrahedron 69 (2013) 5136e5143
Table 5 (continued )
Entry
R
Product
Time (d)
4 (4)
Yieldb (%)
17 (8)
eec (%)
71 (42)
anti/synd
14
p-CH3OeC6H4
82:18 (60:40)
15
p-CH3eC6H4
4 (4)
28 (14)
86 (82)
90:10 (89:11)
a
The reactions were performed with aromatic aldehyde (0.4 mmol), cyclohexanone (1 mL), catalyst (0.02 mmol), and water (100
were performed neat with no water.
m
L) at ꢀ20 ꢁC. The results in parentheses
b
Isolated yield.
Determined by chiral HPLC analysis.
Determined by H NMR.
c
d
Table 6
Direct aldol reactions between aromatic aldehydes and cyclopentanone promoted by organocatalyst 1ba
Entry
1
R
Product
Time (d)
4
Yieldb (%)
95
eec (%)
anti/synd
o-NO2eC6H4
<5:98
30:70
2
3
m-NO2eC6H4
2
2
97
83
37:97
34:66
29:71
p-NO2eC6H4
18:d
4
5
p-CNeC6H4
p-CF3eC6H4
2
2
99
99
34:96
62:95
31:69
36:64
6
7
8
9
p-CleC6H4
p-BreC6H4
o-BreC6H4
p-FeC6H4
2
2
2
2
99
99
99
99
46:97
47:98
25:98
56:75
32:68
34:66
34:66
52:48

T. He et al. / Tetrahedron 69 (2013) 5136e5143
5141
Table 6 (continued )
Entry
R
Product
Time (d)
Yieldb (%)
eec (%)
anti/synd
10
2,6-CleC6H3
2
94
94
99:1
11
12
Ph
4
4
87
45
35:97
11:96
53:47
55:46
p-CH3OeC6H4
13
14
p-CH3eC6H4
4
2
91
97
36:95
54:82
27:73
44:56
3-Pyridinyl
15
16
4-Pyridinyl
3-Thienyl
2
4
25
85
14:90
22:88
26:74
49:51
17
2-Furyl
4
50
d:94
45:55
a
The reactions were performed with aromatic aldehyde (0.4 mmol), cyclopentanone (1 mL), catalyst (0.02 mmol), and water (100
Isolated yield.
Determined by chiral HPLC analysis.
Determined by H NMR.
m
L) at ꢀ20 ꢁC.
b
c
d
in hertz (Hz). HPLC was carried out using a Shimadzu organizer
consisting of an LC-2010A HT Integrator and an UV/VIS Detector.
Chiralcel AD-H, OD-H, and AS-H columns were purchased from Daicel
Chemical Industries, Ltd. Electrospray ionization (ESI) mass spec-
trometry experiments were performed on Bruker Daltonics Bio TOF
mass spectrometer. Column chromatography was conducted with
silica gel (300e400 mesh). The reactions were monitored by thin
layer chromatography (TLC). Chemicals and solvents were purchased
from commercial suppliers or purified by standard techniques.
4.2. Typical procedure for the enantioselective aldol reaction
A mixture of catalyst 1b (0.012 g, 0.02 mmol), aldehyde
Fig. 1. The photos of the reaction medium in the absence (left) and presence (right) of
the catalyst 1b. A: before vortexing; B: 30 s after vortexing.
(0.4 mmol), ketone (1 mL), and water (100
m
L) was stirred at ꢀ20 ꢁC.
The reaction mixture was stirred until completion, as suggested by
TLC analysis. The resulting reaction mixture was directly passed
through a short silica gel column to get the pure aldol product.
4. Experimental section
4.1. General information
4.3. General procedure for the preparation of the catalysts (1a
and 2a selected as examples)
1H NMR spectrawere recorded on Bruker (400 MHz and 600 MHz)
spectrometers in CDCl3. 13C NMR (100 MHz) data were collected with
complete proton decoupling. Chemical shifts for protons are reported
in parts per million (ppm) from tetramethylsilane (TMS) with the
residual CHCl3 resonance as internal reference, coupling constants (J)
4.3.1. Representative procedure for the preparation of catalyst
1a. Ethylenediamine 294
mL (1.8 mmol) and triethylamine 278 mL
(2.0 mmol) were dissolved in 100 mL DCM followed by slow

5142
T. He et al. / Tetrahedron 69 (2013) 5136e5143
Fig. 2. Atomic force microscopy (AFM) of the reaction system in the absence (A) and presence of 10% (v/v) water (B).
Fig. 3. Transmission electron microscopy (TEM) of the reaction medium in the presence of the catalyst 1b and water 10% (v/v) after vortexing.
addition of 0.81 g cholesteryl chloroformate (1.8 mmol) pre-
dissolved in 25 mL DCM at 0 ꢁC. The reaction mixture was stirred
overnight at ambient temperature. The solution was washed with
1 N NaOH (2ꢂ125 mL) and brine and then dried over anhydrous
Na2SO4. Evaporation of the solvent gave cholesteryl (2-
aminoethyl)-carbamate (0.83 g, 1.7 mmol, 94%).
40 mL, at ꢀ15 ꢁC, were slowly added 0.65 mL of NMM (5.5 mmol)
and 0.67 mL of isobutyl chlorofomate (5.0 mmol). After the solution
was stirred for 10 min, L-valine methyl ester 0.92 g (5.5 mmol),
which was dissolved in NMM 0.65 mL (5.5 mmol) and 60 mL THF,
was added to the reaction mixture. After 30 min, the reaction
mixture was allowed to warm to room temperature and stirred
overnight. The solution was concentrated under reduced pressure
and the residue was re-dissolved in ethyl acetate (50 mL). The so-
lution was washed with saturated NaHCO3 solution, brine, 1 N citric
acid solution, and water (50 mL each). The organic layer was dried
over anhydrous Na2SO4 and concentrated to give a white solid
1.61 g (4.9 mmol, 98%). This white solid was dissolved in 30 mL
methanol and cooled to 0 ꢁC followed by the addition of 2 N KOH
solution 15 mL. The reaction mixture was allowed to warm to room
temperature and stirred for 4 h. The methanol was removed under
reduced pressure, the residue was cooled to 0 ꢁC, and HCl 60 mL
(5%) was added to the mixture. The aqueous layer was extracted
with ethyl acetate (3ꢂ60 mL). The combined organic layer was
dried over anhydrous Na2SO4 and concentrated to yield BocePro-
ValeOH as a white solid 1.32 g (4.2 mmol, 85%).
Cholesteryl (2-aminoethyl)carbamate 0.83 g (1.7 mmol), N-Boc-L-
proline 0.36 g (1.7 mmol), and EDCI 0.50 g (2.6 mmol) were dissolved
in 50 mL DCM and stirred overnight at ambient temperature. The
solvent was removed by reduced pressure and the residue purified
by column chromatography on silica gel (petroleum ether/ethyl ac-
etate: 1:2) to yield Boc-1a as a white solid (0.91 g, 1.4 mmol, 80%).
Boc-1a 0.91 g (1.4 mmol) was dissolved in 10 mL of a trifluoro-
acetic acid (TFA) and DCM mixture (1:4, v/v). The reaction was
allowed to proceed at room temperature with stirring for 6 h. Then
the solvent was completely removed by reduced pressure and the
residue was washed with diethyl ether several times yielding
a white solid. The white precipitate was dissolved in CHCl3 and
washed with saturated NaHCO3 solution (3ꢂ10 mL), water, and
brine (10 mL each). The solution was finally dried over anhydrous
Na2SO4 and concentrated to give catalyst 1a as a white solid (0.68 g,
1.2 mmol, 87%).
Cholesteryl (2-aminoethyl) carbamate 1.98
g (4.2 mmol),
BocePro-ValeOH 1.32 g (4.2 mmol), and EDCI 1.21 g (6.3 mmol)
were dissolved in 100 mL DCM and stirred overnight at ambient
temperature. The solvent was removed by reduced pressure and
the residue purified by column chromatography on silica gel
4.3.2. Representative procedure for the preparation of catalyst 2a. To
a stirred solution of N-Boc-L-proline 1.07 g (5.0 mmol) and THF

T. He et al. / Tetrahedron 69 (2013) 5136e5143
5143
€
3. (a) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (b) Li, C.-J. Chem. Rev. 2005, 105,
(petroleum/ethyl acetate: 1:2) to yield Boc-2a as a white solid
2.23 g (2.9 mmol, 70%).
ꢀ
3095; (c) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687; (d) Hernandez, J. G.;
Juaristi, E. Chem. Commun. 2012, 5396.
Boc-2a 2.23 g (2.9 mmol) was dissolved in 20 mL of a trifluoro-
acetic acid (TFA) and DCM mixture (1:4, v/v). The reaction was
allowed to proceed at room temperature with stirring for 6 h. Then
the solvent was completely removed by reduced pressure and the
residue was re-dissolved in CHCl3 washed with saturated NaHCO3
solution (3ꢂ20 mL), water, and brine (20 mL each). The solution
was finally dried over anhydrous Na2SO4 and concentrated to give
yellowish viscous residue, which was subjected to flash column
chromatography on silica to give catalyst 2a as a white solid 1.74 g
(2.6 mmol, 89%).
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Acknowledgements
This work was financially supported by the National Program on
Key Basic Research Project of China (973 Program, 2013CB328900),
the National Science Foundation of China (Nos. 21001077 and
21021001), Specialized Research Fund for the Doctoral Program of
Higher Education (20100181120040), and State Key Lab of Oral
Diseases (Sichuan University) (SKLODSCUKF2012-02). We also
thank Analytical & Testing Center of Sichuan University for NMR
analysis. We thank Prof. Jason J. Chruma (Sichuan University) for
valuable assistance with manuscript preparation.
Supplementary data
ꢀ
Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun. 2002, 3024; (t) Almas¸ i,
ꢀ
D.; Alonso, D. A.; Balaguer, A.-N.; Najera, C. Adv. Synth. Catal. 2009, 351, 1123.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.04.078.
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