Preparation of immobilized L-prolinamide via enzymatic polymerization of phenolic L-prolinamide and evaluation of its catalytic performance for direct asymmetric aldol reaction

Article abstract of DOI:10.1002/chir.22302

Phenolic L-prolinamide was allowed to participate in enzymatic polymerization with horseradish peroxidase as the catalyst, generating immobilized L-prolinamide. The catalytic performance of the resultant polymer-supported L-prolinamide for direct asymmetr

Full text of DOI:10.1002/chir.22302

CHIRALITY 26:209–213 (2014)
Preparation of Immobilized L-Prolinamide Via Enzymatic
Polymerization of Phenolic L-Prolinamide and Evaluation of Its
Catalytic Performance for Direct Asymmetric Aldol Reaction
1
1
1
1,2
CHENGKE QU, WENSHAN ZHAO, LEI ZHANG, AND YUANCHEN CUI
*
1
College of Chemistry and Chemical Engineering, Henan University, Kaifeng, China
Key Laboratory of Ministry of Education for Special Functional Materials, Henan University, Kaifeng, China
2
ABSTRACT
Phenolic L-prolinamide was allowed to participate in enzymatic polymerization
with horseradish peroxidase as the catalyst, generating immobilized L-prolinamide. The catalytic
performance of the resultant polymer-supported L-prolinamide for direct asymmetric aldol
reaction between aromatic aldehyde and cyclohexanone was studied. The results show that as
prepared L-prolinamide can catalyze the aldol reaction at room temperature in the presence of
H O. Relevant aldol addition products are obtained with good yields (up to 91%), high
2
diastereoselectivities (up to 6:94 dr), and medium enantioselectivities (up to 87% ee). Moreover,
the title polymer-supported catalyst can be recovered and reused for at least five cycles while the
activity remains almost unchanged. Chirality 26:209–213, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: L-prolinamide; polymerization; polymer-supported catalyst; asymmetric aldol
reaction
INTRODUCTION
EXPERIMENTAL
General
A direct asymmetric aldol reaction, involving a nonactivated
ketone as nucleophile, is one of the most efficient reactions
for affording C-C chains, and it has been extensively used in
Commercial-grade reagents and solvents were used as received except-
ing that a specific purification procedure was recommended. HRP (RZ =
2.5, activity = 200 U/mg) was purchased from Shanghai Guoyuan Bio-
technology (China) and used without further purification. Thin-layer
chromatograph (TLC) analysis was conducted with GF254 silica gel
plates. Infrared spectra were recorded with an Avatar360 Fourier trans-
form infrared spectrometer (FTIR; Nicolet, Thermo Scientific, Pittsburgh,
PA). Nuclear magnetic resonance (NMR) spectra were obtained with a
1
–7
the synthesis of natural products and drug molecules.
Among the various catalysts for direct asymmetric aldo8l
reaction, a series of organocatalysts derived from L-proline
are of particular significance. This is why many efforts have
been made to modify the structure of L-proline so as to
improve selectivity and reusability, reduce load, and avoid
1
Bruker Avance 400 M system, and the chemical shifts of H-NMR spectra
9–14
the use of organic solvent.
To overcome these drawbacks,
were reported in relation to tetramethyl silane (δ = 0). Polymer molecular
weight and the poly-dispersity index (PDI) were measured with a gel
permeation chromatograph coupled with a static laser light scattering
unit (GPC-SLS; DAWN EOS and OPTILAB rEX, Wyatt Technology, Santa
Barbara, CA; flow rate of fluent tetrahydrofuran: 1.0 mL/min). Melting
points (m.p.) were measured with an X-6 melting point apparatus. Analyt-
ical high-performance liquid chromatograph (HPLC) analysis was
performed with an Agilent 1100 facility equipped with a diode array ultra-
violet detector (Daicel, Tokyo, Japan, Chiralpak AD-H (AS-H) was used
for HPLC analysis).
researchers also have made attempts to graft organocatalysts
1
5–18
with suitable supports.
The resultant immobilized
organocatalysts offer some advantages over small organic cat-
alysts, such as recyclability, simple reaction set-up plus easy
experimental procedure, and nontoxicity. In this sense,
proline-derived organocatalysts, immobilized by polysty-
1
9–22
23,24
25
26,27
rene,
even ionic liquid,
synthesis of the supported proline catalysts via acrylic
polyethyleneglycol,
chitosan, silica,
and
2
8,29
may be particularly interesting. The
copolymerization3
0,31
and the preparation of helical poly
phenylacetylene)s bearing cinchona alkaloid via the
polymerization of corresponding phenylacetylenes
provide recent examples for synthesizing proline-derived
organocatalysts.
In the present research, we chose phenolic L-prolinamide,
while the prolinamide was considered as an active and highly
Preparation of the Catalysts
The procedures for preparing polymer-supported L-prolinamide a are
outlined in Scheme 1, where three major steps are involved. First, acyl
2
chloride 3 was synthesized by the reaction of Fmoc-L-Pro with SOCl ;
and then 3 was allowed to react with p-aminophenol to give Fmoc-
protected phenolic L-prolinamide 2. Second, the N-Fmoc protecting
group of 2 was removed with diethylamine. Finally, phenolic L-
prolinamide 1 (3.0 mmol) was dissolved in 3 mL buffer solution (phos-
phate, pH = 7) while 9 mL of dioxane was added as a cosolvent. Into the
resultant solution was then added the enzyme solution of HRP (3.0 mg)
in buffer (3 mL), followed by addition of 0.25 mL of 5% hydrogen peroxide
every 5 min for a total cycles of 14. The resultant mixture was stirred at
(
32,33
stereoselective catalyst for the direct aldol reaction in the
presence of water,3
4–39
as a monomer to synthesize poly-
mer-supported L-prolinamide via the enzymatic polymeriza-
tion catalyzed by horseradish peroxidase (HRP).
4
0,41
Such
an approach is facile and competitive. This paper reports the
synthesis of polymer-supported L-prolinamide and the evalua-
tion of its catalytic performance for direct asymmetric aldol
reaction between aromatic aldehyde and cyclohexanone at
room temperature in the presence of water. The recyclability
of the catalyst was also evaluated carefully.
*
Correspondence to: Yuanchen Cui, College of Chemistry and Chemical Engi-
neering, Henan University, Kaifeng 475004, China. E-mail: yccui@henu.edu.cn
Received for publication 23 October 2013; Accepted 8 January 2014
DOI: 10.1002/chir.22302
Published online 12 March 2014 in Wiley Online Library
(wileyonlinelibrary.com).
©
2014 Wiley Periodicals, Inc.

2
10
QU ET AL.
DCM. After being dried in an oven for 24 h, the catalyst could be reused
directly without further purification.
RESULTS AND DISCUSSION
The aldol reaction between 4-nitrobenzaldehyde and cyclo-
hexanone was adopted as a model reaction to evaluate the
catalytic performance of the synthesized polymer-supported
L-prolinamide. Table 1 presents the catalytic performance
of the synthesized L-prolinamide catalyst for the above-
mentioned aldol reaction in various solvent systems. It
could be seen that the synthesized L-prolinamide catalyst pos-
Scheme 1. Routes to synthesis of polymer-supported organocatalyst.
sessed the best catalytic efficiency in H O (Entry 1, 87% yield,
2
1
0:90 dr, and 83% ee), but it exhibited a reduced catalytic effi-
ciency in organic solvents. Particularly, the aldol product was
obtained with low yields (27%–43%) and poor stereoselectivities
(43%–69% ee) in polar solvents or less polar solvents; what’s
more, the stereoselectivity of the catalyst remained almost
unchanged in the aqueous solution of 2 mmol/L Tween-20
room temperature (r.t.) for 24 h to allow polymerization yielding brown
powdery precipitates. At the end of the polymerization reaction, dioxane
was evaporated in vacuo, and the crude product was collected by leaching
and washing sequentially with water, petroleum ether, and ethylacetate.
The target product, polymer-supported L-prolinamide catalyst a, was
obtained after the washed product was dried in a vacuum oven until the
weight remained constant. The functional groups were confirmed by
the Fourier transform infrared (FT-IR) spectra. It can be seen from
(
Entry 8).
Table 2 shows the results of a series of reactions for
optimizing the reaction conditions. Initial tests were
conducted using different loading of cyclohexanone as nucle-
ophile (Entries 1–4). When the dosage of cyclohexanone was
fixed at 5 equivalent (equiv.), the aldol product was obtained
with a higher ee value (83%); and lowering dosage of the nu-
cleophile led to reduced reaction rate (Entry 4). Besides,
the lower ee value was obtained for the reaction performed
-1
Figure 1 (m) that the broad band at around 3289 cm was assigned to
-
-
1
1
hydroxyl and amino of the polymer, the infrared absorption of 1674 cm
was assigned to the carbonyl of amido bond, and peaks of 1514 cm
-
1
and 1449 cm were assigned to the benzene ring. The peaks at
201 cm and 1135 cm were due to the C-O-C and C-OH linkage.
-
1
-1
1
Gel permeation chromatograph (GPC) analysis showed that L-prolinamide
organocatalyst a has a weight-average molecular weight (M ) of 15450
w
and PDI value of 1.84.
without H O (Entry 5), while the stereoselectivity of the
2
catalyst was improved significantly when traces of H O were
2
added into the reaction system (Entry 6). This might be
because H O suppressed the formation of parasitic species,
2
General Procedure for Direct Aldol Reaction
thereby decreasing the relative concentration of some
intermediates like oxazolidinones and increasing the catalyst
Substituted benzaldehyde (0.2 mmol) was added into the mixture of
cyclohexanone, a certain amount of catalyst, and the solvent. The mixture
was stirred at r.t., and the reaction system was detected by TLC (ethyl
acetate/petroleum ether = 1:2 (volume ratio)). Upon completion of the
reaction, the product was filtered and extracted with ethyl acetate; then
20,42–44
concentration.
TABLE 1. Screening solvent for the asymmetric Aldol reaction
the organic layer was dried over Na
2
SO
4
, filtered, concentrated, and puri-
a
between cyclohexanone and p-nitrobenzaldehyde
fied by TLC on a silica gel (ethyl acetate/petroleum ether) giving pure al-
dol product.
Recyclability of Polymer-Supported L- Prolinamide Catalyst
At the end of the aldol reaction between cyclohexanone and 4-
nitrobenzaldehyde, the catalyst was filtered in vacuum and washed with
b
c
c
Yield
(%)
dr (syn/
anti)
ee (%)
(anti)
Entry
Solvent
1
2
3
H
2
O
87
43
32
10:90
31:69
24:76
83
45
57
Isopropanol
Dimethylformamide
(
DMF)
Dimethyl sulphoxide
DMSO)
CH CN
4
27
27:73
43
(
5
6
7d
8
3
29
41
35
89
34:66
16:84
40:60
12:88
58
69
51
78
Petroleum ether
Toluene
H O-Tween-20
2
aReaction performed at 0.2 mmol scale of aldehyde and 5 equiv. of cyclohexa-
none in the presence of 10 mol% catalyst in 500 μL undistilled solvent.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).
d
Fig. 1. FT-IR spectra of catalyst a (m) and poly(4-aminophenol) (n).
Chirality DOI 10.1002/chir
The aqueous solution of Tween-20 (2 mmol/L) was used as solvent.

NOVEL L-PROLINAMIDE CATALYST FOR ALDOL REACTION
211
TABLE 2. Screening the amount of cyclohexanone, solvent and
TABLE 4. Recovery and reuse of polymer-supported L-
a
catalyst for the asymmetric Aldol reaction between cyclohexa-
prolinamide catalyst
a
none and 4-nitrobenzaldehyde
b
c
c
Entry
Cycle
Yield (%)
dr (syn./anti.)
ee (%) (anti.)
c
dr
(syn./
anti.)
b
c
1
2
3
4
5
1
2
3
4
5
91
90
92
83
89
11:89
9:91
8:92
10:90
11:89
87
84
86
82
85
Solvent
(μL)
Cyclohexanoe
(equiv.)
Yield
(%)
ee (%)
(anti.)
Entry
1
2
3d
4
5
500
500
500
500
neat
40
120
500
500
40
15
10
5
2.5
5
5
5
5
5
5
88
90
84
67
89
91
85
86
88
89
11:89
10:90
10:90
10:90
14:86
11:89
10:90
8:92
80
78
83
78
73
87
81
78
79
76
aReaction performed at 0.2 mmol scale of aldehyde and 5 equiv. of cyclohexa-
none (cyclopentanone) in the presence of 10 mol% catalyst in 40 μL of H
2
O.
b
Isolated yield.
6
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).
7e
8f
9 g
13:87
12:88
1
1
The effect of the amount of catalyst is summarized in
Table 2. It can be seen that decreasing the amount of catalyst
to 2.5 mol% led to a lower ee value, as did increasing the
amount of catalyst to 25 mol% (Entries 3, 8–9). In combination
with the results shown in Table 1, the optimized reaction con-
ditions for the title aldol reaction were suggested as catalyst
aReaction performed at 0.2 mmol scale of aldehyde and 5 equiv. of cyclohexa-
none in the presence of 10 mol% catalyst in 500 μL H
2
O.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).
d
The reaction time was 144 h.
e
f
Reaction performed in the presence of 2.5 mol% catalyst.
Reaction performed in the presence of 25 mol% catalyst.
dosage of 10 mol% and 5 equiv. of cyclohexanone while H O
2
g
was introduced into the reaction system. Moreover, by
comparing with phenolic L-prolinamide 1 the catalyst tested
under the optimized reaction conditions (Entry 11 in Table 2),
we could draw a conclusion that the polymer-supported
catalyst possesses better stereoselectivity but lower catalytic
activity than the monomer 1.
Reaction catalyzed by monomer 1, and the reaction time was 24 h.
TABLE 3. Asymmetric Aldol reactions catalyzed by polymer-
a
supported L-prolinamide
In the presence of cyclohexanone (cyclopentanone) as the
donor, medium stereoselectivity was obtained with different
aromatic aldehydes (Table 3). As to some benzaldehydes
with strong electron-withdrawing substituents, the reaction
was completed with good diastereoselectivity, moderate
enantioselectivity, and high yield (Entries 1–4). However, a
low diastereoselectivity was recorded for reactions involving
benzaldehyde containing weak electron-withdrawing groups,
and the reaction rate in these cases was also reduced (Entries
b
c
c
Entry
R
Yield (%)
dr (syn/anti)
ee (%) (anti)
6
–8). When benzaldehyde and 4-anisaldehyde were used as
1
2
3
4
5
6
7
8
9
1
1
1
1
1
4-NO
2,4-NO
2
91
90
86
83
73
46
41
43
27
25
68
89
87
73
11:89
9:91
9:91
6:94
9:91
22:78
15:85
16:84
39:61
22:78
—
87
82
88
87
80
82
83
80
67
75
32
87
86
80
aldol acceptor, the enantioselectivity remained moderate,
but the yield decreased significantly (Entries 9–10). To
our disappointment, when the acetone was used as aldol
donor the ee value just was 32% (Entry 11). To broaden
the scope of the methodology, we also adopted polymer-
supported L-prolinamide to catalyze the direct asymmetric
aldol reaction between cyclopentanone and benzaldehyde,
and we found that the aldol products were obtained with
good yield (up to 89%) and enantioselectivity (up to 87%)
in the presence of nitrobenzaldehydes as electrophile
(Entries 12–14).
The recyclability of the polymer-supported L-prolinamide
catalyst under the optimized reaction conditions was also
evaluated and the results are listed in Table 4. It could be
seen that the prepared polymer-supported L-prolinamide
retained almost unchanged activity, enantioselectivity, and
diastereoselectivity after it was used for at least five cycles,
which indicates that the title catalyst was well reusable.
Chirality DOI 10.1002/chir
2
2-NO
3-NO
4-CN
4-F
2
2
4-Cl
4-Br
4-H
0d
4-OCH
3
1e
2e
3e
4-NO
4-NO
2-NO
3-NO
2
2
2
2
40:60
17:83
33:67
4
aReaction performed at 0.2 mmol scale of aldehyde and 5 equiv. of cyclohexa-
none (cyclopentanone) in the presence of 10 mol% catalyst in 40 μL of H
2
O.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H or AS-H).
d
Acetone used as the nucleophile.
e
Cyclopentanone used as the nucleophile.

2
12
QU ET AL.
1
6. Kristensen TE, Hansen T. Polymer-supported chiral organocatalysts: syn-
thetic strategies for the road towards affordable polymeric immobilization.
Eur J Org Chem 2010;2010:3179–3204.
CONCLUSION
In summary, we have successfully designed a new strategy
for the immobilization of L-prolinamide, which is based on the
enzymatic polymerization of phenolic L-prolinamide in the
presence of HRP as the catalyst. The resultant polymer-
supported L-prolinamide was tested as an organocatalyst for
direct asymmetric aldol reaction between aromatic
aldehyde and cyclohexanone. The findings show that the
synthesized polymer-supported L-prolinamide can catalyze
the aldol reaction under investigation at r.t. in the
1
7. Trindade AF, Gois PMP, Afonso CAM. Recyclable stereoselective cata-
lysts. Chem Rev 2009;109:418–514.
18. Gruttadauria M, Giacalone F, Noto R. Supported proline and
proline-derivatives as recyclable organocatalysts. Chem Soc Rev
2
008;37:1666–1688.
1
2
9. Kehat T, Goren K, Portnoy M. Effects of dendritic interface on
enantioselective catalysis by polymer-bound prolines. New J Chem
2012;36:394–401.
0. Banon-Caballero A, Guillena G, Najera C. Solvent-free direct
enantioselective aldol reaction using polystyrene-supported N-
presence of H O, giving good yield (up to 91%), high
2
diastereoselectivity (up to 6:94 dr), and medium
enantioselectivity (up to 87% ee) of the relevant aldol ad-
ducts. In addition, the prepared polymer-supported catalyst
can be recovered and reused for at least five cycles while
the activity remains almost unchanged, showing promising
potential as a highly efficient organocatalyst for the afore-
mentioned aldol reaction. Further studies on the influence
for the catalytic performance of the copolymerization and
other phenolic L-prolinamide like ortho-aminophenol-L-
prolinamide are under way.
sulfonyl-(Ra)-binam-d-prolinamide as
010;12:1599–1606.
a
catalyst. Green Chem
2
2
2
1. Liu Y-X, Sun Y-N, Tan H-H, Tao J-C. Asymmetric aldol reaction catalyzed
by new recyclable polystyrene-supported -proline in the presence of water.
Catal Lett 2008;120:281–287.
2. Li J, Yang G, Qin Y, Yang X, Cui Y. Recyclable Merrifield resin-
supported thiourea organocatalysts derived from l-proline for
direct asymmetric aldol reaction. Tetrahedron: Asymmetry
2
011;22:613–618.
2
2
3. Benaglia M, Celentano G, Cozzi F. Enantioselective aldol condensations
catalyzed by poly(ethylene glycol)-supported proline. Adv Synth Catal
2001;343:171–173.
4. Gu L, Wu Y, Zhang Y, Zhao G. A new class of efficient poly(ethylene-
glycol)-supported catalyst based on proline for the asymmetric
Michael addition of ketones to nitrostyrenes. J Mol Catal A Chem
SUPPORTING INFORMATION
2
007;263:186–194.
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
2
5. Zhang H, Zhao W, Zou J, Liu Y, Li R, Cui Y. Aldol reaction catalyzed by a
hydrophilic catalyst in aqueous micelle as an enzyme mimic system.
Chirality 2009;21:492–496.
2
6. Monge-Marcet A, Cattoen X, Alonso DA, Najera C, Man MWC,
Pleixats R. Recyclable silica-supported prolinamide organocatalysts
for direct asymmetric Aldol reaction in water. Green Chem
LITERATURE CITED
1
. Doyle AG, Jacobsen EN. Small-molecule H-Bond donors in asymmetric
catalysis. Chem Rev 2007;107:5713–5743.
. Hélène P. Asymmetric organocatalysis. Tetrahedron 2007;63:9267–9331.
. Mukherjee S, Yang JW, Hoffmann S, List B. Asymmetric enamine cataly-
sis. Chem Rev 2007;107:5471–5569.
. Hernandez JG, Juaristi E. Recent efforts directed to the development of
more sustainable asymmetric organocatalysis. Chem Commun
2
012;14:1601–1610.
2
7. Bortolini O, Caciolli L, Cavazzini A, Costa V, Greco R, Massi A, Pasti L.
Silica-supported 5-(pyrrolidin-2-yl)tetrazole: development of organocatalytic
processes from batch to continuous-flow conditions. Green Chem
2
3
2012;14:992–1000.
4
2
8. Kochetkov SV, Kucherenko AS, Kryshtal GV, Zhdankina GM,
Zlotin SG. Simple ionic liquid supported c2-symmetric
bisprolinamides as recoverable organocatalysts for the asymmetric
2
012;48:5396–5409.
5
6
7
8
9
. Gopalaiah K, Kagan HB. Use of nonfunctionalized enamides and
enecarbamates in asymmetric synthesis. Chem Rev 2011;111:4599–4657.
aldol reaction in the presence of water. Eur
012;2012:7129–7134.
J Org Chem
2
. Bisai V, Bisai A, Singh VK. Enantioselective organocatalytic aldol reaction
using small organic molecules. Tetrahedron 2012;68:4541–4580.
. Sergei GZ, Alexander SK, Irina PB. Organocatalysis of asymmetric aldol
reaction. Catalysts and reagents. Russ Chem Rev 2009;78:737.
. List B, Lerner RA, Barbas CF. Proline-catalyzed direct asymmetric aldol
reactions. J Am Chem Soc 2000;122:2395–2396.
. Zhang L, Luo S, Cheng J-P. Non-covalent immobilization of asymmetric
organocatalysts. Catal Sci Technol 2011;1:507–516.
2
9. Siyutkin DE, Kucherenko AS, Zlotin SG. Ionic liquid organocatalysts.
comprehensive enantioselective organocatalysis. Hoboken, NJ: Wiley-
VCH; 2013. p 617–650.
0. Kristensen TE, Vestli K, Jakobsen MG, Hansen FK, Hansen T. A general
approach for preparation of polymer-supported chiral organocatalysts via
acrylic copolymerization. J Org Chem 2010;75:1620–1629.
3
31. Kristensen TE, Vestli K, Fredriksen KA, Hansen FK, Hansen T. Synthesis
of acrylic polymer beads for solid-supported proline-derived
organocatalysts. Org Lett 2009;11:2968–2971.
32. Miyake GM, Iida H, Hu H-Y, Tang Z, Chen EYX, Yashima E. Synthesis of
helical poly(phenylacetylene)s bearing cinchona alkaloid pendants and
their application to asymmetric organocatalysis. J Polym Sci A: Polym
Chem 2011;49:5192–5198.
1
1
1
0. Zhao Q, Lam Y-h, Kheirabadi M, Xu C, Houk KN, Schafmeister CE. Hy-
drophobic substituent effects on proline catalysis of aldol reactions in wa-
ter. J Org Chem 2012;77:4784–4792.
1. Fu Y-Q, An Y-J, Liu W-M, Li Z-C, Zhang G, Tao J-C. Highly diastereo- and
enantioselective direct aldol reaction catalyzed by simple amphiphilic pro-
line derivatives. Catal Lett 2008;124:397–404.
2. Viozquez SF, Banon-Caballero A, Guillena G, Najera C, Gomez-Bengoa E.
Enantioselective direct aldol reaction of [small alpha]-keto esters cata-
lyzed by (Sa)-binam-d-prolinamide under quasi solvent-free conditions.
Org Biomol Chem 2012;10:4029–4035.
3
3. Tang Z, Iida H, Hu H-Y, Yashima E. Remarkable enhancement of
the enantioselectivity of an organocatalyzed asymmetric Henry
reaction assisted by helical poly(phenylacetylene)s bearing cin-
chona alkaloid pendants via an amide linkage. ACS Macro Lett
2012;1:261–265.
1
3. Xu J-W, Fu X-K, Hu X-Y, Wu C-L. Simple and facile l-prolinamides
derived from achiral cycloalkylamines as organocatalysts for the
highly efficient large-scale asymmetric direct aldol reactions. Catal
Lett 2011;141:1156–1163.
4. Lei M, Xia S, Wang J, Ge Z, Cheng T, Li R. An efficient dipeptide-catalyzed
direct asymmetric aldol reaction of equimolar reactants in solid media.
Chirality 2010;22:580–586.
34. Paladhi S, Das J, Mishra PK, Dash J. Multifunctional “click” prolinamides:
a new platform for asymmetric aldol reactions in the presence of water
with catalyst recycling. Adv Synth Catal 2013;355:274–280.
3
5. Fotaras S, Kokotos CG, Tsandi E, Kokotos G. Prolinamides bearing thio-
urea groups as catalysts for asymmetric aldol reactions. Eur J Org Chem
2011;2011:1310–1317.
1
1
3
6. Gao J, Liu J, Tang J, Jiang D, Li B, Yang Q. Chirally functionalized hollow
nanospheres containing l-prolinamide: synthesis and asymmetric cataly-
sis. Chem Eur J 2010;16:7852–7858.
5. Itsuno S, Parvez MM, Haraguchi N. Polymeric chiral organocatalysts.
Polym Chem 2011;2:1942–1949.
Chirality DOI 10.1002/chir

NOVEL L-PROLINAMIDE CATALYST FOR ALDOL REACTION
213
3
3
7. Zhang S-p, Fu X-k, Fu S-d. Rationally designed 4-phenoxy substituted
prolinamide phenols organocatalyst for the direct aldol reaction in water.
Tetrahedron Lett 2009;50:1173–1176.
8. Moorthy JN, Saha S. Highly diastereo- and enantioselective aldol
reactions in common organic solvents using N-arylprolinamides as
organocatalysts with enhanced acidity. Eur J Org Chem 2009;2009(5):
Advances in polymer science. Berlin Heidelberg: Springer; 1995.
p 1–30.
41. Matsumura S. Enzyme-catalyzed synthesis and chemical recycling of
polyesters. Macromol Biosci 2002;2:105–126.
42. Zotova N, Franzke A, Armstrong A, Blackmond DG. Clarification of the Role of
water in proline-mediated aldol reactions. J Am Chem Soc 2007;129:15100–15101.
3. Mlynarski J, Paradowska J. Catalytic asymmetric aldol reactions in aque-
7
39–748.
4
3
9. Lei M, Shi L, Li G, Chen S, Fang W, Ge Z, Cheng T, Li R. Dipeptide-cata-
lyzed direct asymmetric aldol reactions in the presence of water. Tetrahe-
dron 2007;63:7892–7898.
0. Kobayashi S, Shoda S-i, Uyama H. Enzymatic polymerization and
oligomerization. Polymer synthesis/polymer engineering, vol. 121.
ous media. Chem Soc Rev 2008;37:1502–1511.
4
4. Aratake S, Itoh T, Okano T, Nagae N, Sumiya T, Shoji M, Hayashi
Y. Highly diastereo- and enantioselective direct aldol reactions of al-
dehydes and ketones catalyzed by siloxyproline in the presence of
water. Chem Eur J 2007;13:10246–10256.
4
Chirality DOI 10.1002/chir