Direct asymmetric aldol reactions in aqueous media catalyzed by a β-cyclodextrin-proline conjugate with a urea linker

Article abstract of DOI:10.1016/j.tetlet.2014.11.084

Covalently attaching proline to β-CD through a urea linkage resulted in the synthesis of a water-soluble chiral organocatalyst 1 in high yield. Catalytic asymmetric aldol condensations between aldehydes and acetone were carried out under water-containing

Full text of DOI:10.1016/j.tetlet.2014.11.084

Tetrahedron Letters 56 (2015) 243–246
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Tetrahedron Letters
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Direct asymmetric aldol reactions in aqueous media catalyzed
by a b-cyclodextrin–proline conjugate with a urea linker
Kegang Liu a, Guoqi Zhang b,
⇑
a Nanomedicine Group, Medical Intensive Care Unit, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
b Department of Sciences, John Jay College and The Graduate Center of the City University of New York, New York, NY 10019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Covalently attaching proline to b-CD through a urea linkage resulted in the synthesis of a water-soluble
chiral organocatalyst 1 in high yield. Catalytic asymmetric aldol condensations between aldehydes and
acetone were carried out under water-containing conditions by using 5 mol % of 1 as catalyst, and
moderate to high yields and enantioselectivities (up to 99% ee) were achieved for a broad range of
aldehydes. Substrate selectivity was also tested. Recycling experiments were performed to confirm good
recyclability and reusability of the catalyst.
Received 8 October 2014
Revised 13 November 2014
Accepted 17 November 2014
Available online 22 November 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Aldol reaction
b-Cyclodextrin
Proline derivatives
Enantioselectivity
Urea
The direct asymmetric aldol reaction between ketones and
aldehydes is a powerful tool for the construction of carbon–carbon
bonds in synthetic organic chemistry.1 Its great usefulness for the
syntheses of natural products and valuable medicinal intermedi-
ates has promoted the rapid evolution of efficient chiral catalyst
systems,2 among which optically pure proline and its derivatives
have proven to be a class of effective catalysts for the asymmetric
aldol reactions over the past decades.3 However, in most cases the
reactions were performed in organic solvents.4 Water is known as
the important reaction media for most enzymatic reactions in
living systems, and from a viewpoint of green chemistry it has
obvious advantages to use water as a solvent over organic solvents
that are often flammable and toxic. In addition, using water as a
solvent for catalytic organic reactions also makes the catalysts
recyclable and reusable. To develop enzyme mimics and to better
understand the mechanism of the chemistry of life, it is desired
to observe catalysts that can carry out organic transformations
efficiently and selectively in water media.5,6 There were recent
examples on the diastereo- and enantio-selective aldol reactions
in water, however, the ketone substrates have been limited to
cyclohexanone in many cases.7 In contrast, the less active acetone
was rarely used for highly selective aldol reactions in water.
In recent years, b-cyclodextrin (b-CD) has been utilized as an
important carrier for effective aldol organocatalysts such as proline
derivatives to mimic enzyme catalyzed reactions in water.8 b-CD is
water soluble, yet it has a hydrophobic cavity that mimics
hydrophobic pockets in enzyme and can bind hydrophobic organic
substrates in aqueous media. The pioneering work was conducted
by Breslow and co-workers, who reported that assembles of b-CD
and various amino moieties act as Schiff base forming aldolase
mimics to catalyze aldol reactions under buffer conditions.9
Although a few recent examples revealed that inclusion complexes
of b-CD with active proline derivatives catalyzed efficiently
enantio- and diastereo-selective aldol reactions in water,10 cova-
lently linked catalysts containing b-CD and organocatalysts for
asymmetric aldol reactions in water were little reported.11,12 In
2012, Ji and Shen reported two pyrrolidine modified b-CDs that
catalyzed aldol reactions between 4-nitrobenzaldehyde and ace-
tone in medium yields and moderate to good ee values under buf-
fer conditions, and the control of pH values were proven to be
crucial for good stereoselectivities.11 Fernández-Mayoralas and
co-worker also described several proline-b-CD conjugates that
were linked through various amide moieties and tested their
catalytic activity toward asymmetric aldol condensations between
4-nitrobenzaldehyde and dioxanone in water, however, only mod-
erate conversions and low enantioselectivity were achieved.
Although it was observed that one of these catalysts promoted
the reaction of 4-nitrobenzaldehyde and acetone with high conver-
sion, only 6% ee was obtained.12
Herein, we report our efforts in the synthesis of a new proline-
b-CD conjugate 1 covalently linked by a urea spacer (Scheme 1),
⇑
Corresponding author.
E-mail address: guzhang@jjay.cuny.edu (G. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2014.11.084
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

244
K. Liu, G. Zhang / Tetrahedron Letters 56 (2015) 243–246
isolated in 93% yield (Scheme 2, Cbz = benzyloxy carbamate;
OR
O
Bn = benzyl).
OR
The all deprotected 1 is well soluble in water as expected, while
the TBDMS-protected 2 displays poor solubility in water. We next
examined the catalytic activity of the newly synthesized catalysts
toward the asymmetric aldol reactions in water. Initially, the direct
aldol reaction of 4-nitrobenzaldehyde (6a) and acetone was tested
in the presence of 5 mol % of 1 in aqueous media (Scheme 3). Pleas-
ingly, the reaction proceeded smoothly and complete conversion
was observed within 10 h at 0 °C, and the desired aldol product
7a was isolated in 97% yield, along with a good enantiomeric
excess (76% ee) as analyzed by HPLC with a chiral column. Lower-
ing the reaction temperature to À18 °C led to a slightly higher ee
value (82%), although the yield of 7a dropped to 86% after 20 h.
This result is comparable to that obtained from amide-bridging
proline-b-CD conjugate catalysts as previously reported.12 Since 1
is poorly soluble in acetone, an attempted reaction at 0 °C in neat
condition without the addition of water was much sluggish, while
a similar enantioselectivity was revealed. Decreasing the loading
amount of acetone to 5.0 equiv gave a little lower yield but the
same ee value. Therefore, the presence of water is essential to
1-catalyzed reactions by both improving the reactivity and facili-
tating the recycling of catalysts (vide infra). In addition, the less
water-soluble catalyst 2 (5 mol %) was also tested for the reaction
shown in Scheme 3, and the result showed that the reaction was
much slower and only moderate ee value (52%) was observed. A
controlled experiment using 2 as a catalyst in neat condition was
also tested, yet the result remained in the same range. The absolute
configuration of the aldol product 7 was determined to be S by
comparing its optical rotation with the reported data in the
literature.10,11
O
O
OH
HO
HN
6
HN
OH
O
O
HN
1 R=H
CO2H
2 R=TBDMS
Scheme 1. The structures of proline derived b-CD catalysts 1 and 2.
and its application as a water-soluble, effective catalyst for highly
enantioselective aldol reactions between aldehydes and acetone in
aqueous media. Urea and thiourea derivatives have been exten-
sively exploited as excellent organocatalysts for many transforma-
tions, by virtue of their capacity of binding and activating
substrates effectively by hydrogen bonding.13 However, they were
thus far not utilized as linkers between b-CD and proline deriva-
tives for organocatalysis.
The synthetic route for catalyst 1 and its TBDMS protected ana-
log 2 is illustrated in Scheme 2 (TBDMS = t-butyldimethylsiloxy).
The known proline derivative 4 was synthesized according to a
published procedure,14 and it was then taken to react with triphos-
gene under basic condition to afford its isocyanate derivative, to
which a known b-CD derived primary amine 315 was added. The
efficient click reaction between the isocynate derivative and amine
3 allows the formation of a key urea-containing intermediate 5 in
high yield in one pot (two steps, 81%). Starting from 5, the synthe-
sis of 1 requires the following two deprotection steps: firstly 5 was
treated with excess of solid NH4F in methanol under refluxing con-
dition to remove TBDMS protecting groups in the primary face of
b-CD. After removal of excess NH4F by a simple purification pro-
cess, the deprotected intermediate was hydrogenolyzed with 10%
Pd/C to give the desired catalyst 1 in good yield (two steps, 79%).
In addition, an attempt to directly hydrogenate 5 with hydrogen
gas in the presence of 10% Pd/C resulted in the deprotection of only
the N-Cbz and O-Bn groups on proline residue, and thus 2 was
To evaluate the substrate scope of the 1-catalyzed aldol reac-
tions in water, a variety of aldehydes including both aromatic
and aliphatic aldehydes were employed, and the results are sum-
marized in Table 1. The results indicate that not only aromatic
aldehydes but also aliphatic aldehydes undergo the aldol conden-
sation with acetone in moderate and good yields, and good to high
enantioselectivities (up to 99% ee) were achieved in most cases. For
example, the reactions involving various para-substituted benzal-
dehydes having electro-withdrawing groups on the benzene ring
furnished the corresponding aldol adducts in high yields (entries
OR
OR
O
O
O
OR
OH
H2N
OR
HO
HN
6
HN
a
OH
O
O
O
O
O
OH
CO2Bn
HO
N
H2N
6
Cbz
OH
O
CbzN
4
3 R=TBDMS
CO2Bn
5 R=TBDMS
OR
O
OR
O
O
OH
b or c
HO
HN
6
HN
OH
O
O
b, 1 R=H
c, 2 R=TBDMS
HN
CO2H
Scheme 2. Reagents and conditions: (a) Triphosgene, aq NaHCO3/DCM, 0 °C–25 °C, 80%; (b) 1. NH4F, MeOH, reflux, 97%; 2. MeOH/H2O, 10% Pd/C, H2, 81%. (c) MeOH, 10% Pd/C,
H2, 93%.

K. Liu, G. Zhang / Tetrahedron Letters 56 (2015) 243–246
245
Table 2
OH
O
O
Recycling experiments of catalyst 1 for the Aldol reaction between 4-nitrobenzalde-
O
hyde and acetonea
1
H
(5 mol%)
*
H2O, 0oC
OH
*
O
O
O2N
O2N
O
7a
1
(2-3 mol%)
H2O
6a
H
Scheme 3. The asymmetric aldol condensation between 4-nitrobenzaldehyde and
acetone catalyzed by 1.
O2N
O2N
7a
6a
Entry
Loading of 1
Time (h)
T (°C)
Yieldb (%)
eec (%)
Table 1
1
2
3
4
5
6
7
3%
20
20
20
6
8
9
À18
À18
À18
0
0
0
93
95
94
92
91
98
91
69
68
67
63
69
72
73
The direct asymmetric aldol reactions between various aldehydes (6) and acetone
2nd cycle
3rd cycle
2%
2nd cycle
3rd cycle
4th cycle
catalyzed by 1 in watera
OH
*
O
O
O
1 (5 mol%)
R
H
R
H2O
12
0
7
6
a
Condition: 4-nitrobenzaldehyde (0.1 mmol), acetone (0.1 ml),
1 (0.002–
Entry Substrate
Product T (°C) Time (h) Yieldb (%) eec (%)
0.003 mmol, 2–3 mol %), and H2O (0.1 ml).
b
Isolated yield.
1
2
3
4
5
4-NO2C6H4 (6a)
4-CNC6H4 (6b)
4-CF3C6H4 (6c)
4-ClC6H4 (6d)
4-FC6H4 (6e)
7a
7b
7c
7d
7e
7f
À18
0
20
12
24
72
72
72
36
48
48
72
72
48
24
72
24
16
72
8
86
>99
93
30
38
16
62
56
60
32
46
26
73
<5
80
76
10
95
93
96
10
97
82
78
80
77
79
91d
82
94
84
92
76
>99d
86
n.d.
88
91
82d
30
59
66
37
9
c
Determined by HPLC analysis with chiral AD-H column.
25
25
25
25
25
0
aldehyde worked smoothly, affording the corresponding product
in 73% yield and 86% ee (entries 13 and 14, Table 1).
6
C6H5 (6f)
7
8
9
4-MeC6H4 (6g)
4-MeC6H4 (6g)
4-tBuC6H4 (6h)
4-tBuC6H4 (6h)
7g
7g
7h
7h
To better understand the substrate selectivity of the aldol
reactions, we also examined the reactions with several other
substituted aromatic aldehydes other than those described above
(entries 18–22, Table 1). It is worth noting that the enantioselectiv-
ities of products decreased dramatically in the order of para-,
meta-, and ortho-substituted benzaldehydes, and only 9% ee was
detected when 2,6-dichlorobenzaldehyde was used, while high
yield was obtained in this case. The different stereoselectivities
resulting from these aromatic substrates might be attributed to
their different binding abilities with the interior cavity of b-CD
on catalyst 1, consistent with the fact the binding constants
between substituted aromatics and b-CD decrease from para-,
meta- to ortho-substitution.10b,16
25
0
10
11
12
13
14
15
16
17
18
19
20
21
22
4-MeOC6H4 (6i) 7i
cyclo-C6H11 (6j)
i-Bu (6k)
t-Bu (6l)
n-Bu (6m)
n-C5H11 (6n)
n-C8H17 (6o)
2-NO2C6H4 (6p) 7p
3-NO2C6H4 (6q) 7q
3-NO2C6H4 (6q) 7q
25
25
25
25
25
25
25
25
25
À18
25
25
7j
7k
7l
7m
7n
7o
12
16
72
24
2-ClC6H4 (6r)
2,6-Cl2C6H3 (6s) 7s
7r
An obvious advantage of our catalytic system is the facile
recyclability of the catalyst. After completion of the reaction and
subsequent extraction of the product with dichloromethane the
catalyst remaining in the aqueous phase can be reused for the next
cycle of reaction. Several recycling experiments for the reaction
between 4-nitrbenzaldehye and acetone were conducted and the
results are summarized in Table 2. When 3 mol % of 1 was used
instead of 5 mol %, the reaction still underwent smoothly, along
with a slightly reduced ee value. Catalyst 1 has been recycled and
reused for three times with almost no change in reactivity and
enantioselectivity (entries 1–3, Table 2). A similar trend was
observed when the loading amount of 1 was decreased to 2 mol %
for the same reaction at 0 °C over four recycling experiments
(entries 4–7, Table 2).
In conclusion, we have synthesized a new water-soluble b-CD
tethered proline derivative by using urea as a linker. Asymmetric
aldol reactions between a variety of aldehydes and acetone have
been carried out by the new organocatalyst in water and the
results indicated that both aromatic and aliphatic aldehydes are
appropriate substrates for this reaction, giving the corresponding
aldol adducts in reasonable yields and good to high enantioselec-
tivities (76–99% ees). Thanks to its good solubility in water, the cat-
alyst can be facilely recycled and reused several times without
decreasing the reactivity and enantioselectivity.
a
Conditions: aldehyde (0.1 mmol), acetone (0.1 ml), 1 (0.005 mmol. 5 mol %),
and H2O (0.1 ml).
b
Isolated yield: Low or modest yields were due to incomplete reactions.
Determined by HPLC analyses with chiral columns.
Absolute configuration is not determined.
c
d
1–3, Table 1), although the halogenated 4-fluorobenzaldehye and
4-chlorobenzaldehyde gave relatively low yields (entries 4 and 5,
Table 1). The ee values for these reactions vary from 77% to 82%.
The stereoselectivities of benzaldehyde and other electron-rich
benzaldehydes were somewhat higher, probably due to their
higher binding ability with the interior cavity of catalyst 1 (entries
6–11, Table 1). Remarkably, the ee values in these reactions were
found to increase significantly from 76% to 94%, and in the cases
of 4-tolualdehyde and 4-tert-butylbenzaldehyde the highest ees
were found when the reactions were run at 0 °C (entries 7 and
10, Table 1). The isolated yields for products from these reactions
were slightly lower, yet comparable to the previous results in the
literature.11,12 Similarly, aliphatic aldehydes also proceeded well
for the aldol reactions under the same conditions, offering high
enantioselectivities to a range of aliphatic substrates (entries
12–17, Table 1). Interestingly, the reactivities were highly depen-
dent on the structures of substrates. Even though the reaction with
cyclohexanaldehyde provided the highest ee (>99%), the yield was
not ideal in contrast to other aldol adducts (entry 12, Table 1).
Unbranched aliphatic aldehydes underwent well the aldol reac-
tions in high yields (entries 15 and 16, Table 1), but the aldehyde
with a longer alkyl chain was quite unfavored (entry 17, Table 1).
The branched and bulky aldehyde pivaldehyde was found to be
the least reactive substrate for this reaction, whereas isobutyl
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
11.084.

246
K. Liu, G. Zhang / Tetrahedron Letters 56 (2015) 243–246
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