Novel synthesis of carbohydrate-derived organocatalysts and their application in asymmetric aldol reactions

Article abstract of DOI:10.1016/j.catcom.2013.07.011

Carbohydrate as a kind of important chiral scaffold is widely recognized for its obvious advantages cheap and readily available. A new type of prolinamide organocatalysts, derived from carbohydrate, was synthesized in high yield, and the novel organocatalysts were applied to the direct asymmetric aldol reactions of cyclohexanone and various aromatic aldehydes. The corresponding aldol products were obtained in high yields (up to 99%) with excellent diastereoselectivities (up to > 98:2 dr) and enantioselectivities (up to 97% ee) under mild reaction conditions.

Full text of DOI:10.1016/j.catcom.2013.07.011

Catalysis Communications 41 (2013) 106–109
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Novel synthesis of carbohydrate-derived organocatalysts and their
☆
application in asymmetric aldol reactions
Chao Shen a, Hanxiao Liao b, Fangyi Shen b, Pengfei Zhang b,
⁎
a
College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2013
Received in revised form 29 June 2013
Accepted 6 July 2013
Available online 13 July 2013
Carbohydrate as a kind of important chiral scaffold is widely recognized for its obvious advantages cheap and
readily available. A new type of prolinamide organocatalysts, derived from carbohydrate, was synthesized in
high yield, and the novel organocatalysts were applied to the direct asymmetric aldol reactions of cyclohexanone
and various aromatic aldehydes. The corresponding aldol products were obtained in high yields (up to 99%) with
excellent diastereoselectivities (up to N98:2 dr) and enantioselectivities (up to 97% ee) under mild reaction
conditions.
Keywords:
© 2013 The Authors. Published by Elsevier B.V. All rights reserved.
Aldol reaction
Asymmetric catalysis
Carbohydrate
Organocatalyst
1. Introduction
efficiently carried out in the presence of various organocatalysts;
among them, prolinamide-derived organocatalysts generally show
Organocatalysis has seen a tremendous rise in popularity when
measured in publications and hence in references [1,2]. This might indi-
cate that a gap between metal- and enzyme-catalysis existed, which
now is being filled by organocatalysis, offering highly stereoselective
transformations of versatile starting materials, using easy procedures,
although at the expense of generally high catalytic loadings. One of
the main advantages of asymmetric catalysis over other methods is
that products can be selectively synthesized from cheap prochiral
starting materials without undesirable products being formed [3]. A
lot of these chiral catalysts are usually based on chiral backbones that
comprise various organic moieties, such as chiral amino alcohol, cincho-
na alkaloids, diamine, prolinamides and their derivatives [4–7]. Despite
significant efforts devoted to the development of highly active catalysts
aimed at using different catalyst backbones, it has been challenging
to develop more natural, efficient backbones for construction of
chiral catalysts [8]. Thus, the current synthetic strategy often relies
on the derivatization of the available chiral pool of the natural organic
products and the natural compounds as chiral scaffolds for the design
and synthesis of catalysts have received great attention so far [9].
Asymmetric aldol reaction is one of the most important
organocatalytic C-C bond-forming reactions [10,11]. It can be
good catalytic performance [12–18]. In recent years, asymmetric reac-
tions catalyzed by the carbohydrate-based catalysts are the intensively
studied as they have been recognized as versatile starting materials for
chiral auxiliaries, reagents, ligands and organocatalysts [19–22]. The de-
sign and fine-tuning of carbohydrate-based catalysts is facilitated by the
multiple functional groups present within this class of compounds. This
strategy has provided unique ligand moieties which combine the per-
formance of “privileged catalysts” with increased flexibility and accessi-
bility. In 2007, the first examples of carbohydrate-derived urea and
thiourea organocatalysts have appeared in the literature. Bifunctional
urea Schiff base organocatalysts were reported by Becker et al.
[23].In the Strecker reaction of aldimine with trimethylsilyl cyanide,
the organocatalysts yielded product in good ee. In 2010, our research
group described the first application of D-glucosamine-derived amino
alcohols as organocatalysts in the enantioselective aldol reactions of
cyclohexanone with isatin and its derivatives. A variety of isatins were
used as substrates, and the corresponding aldol products were obtained
in excellent chemical yields with high yields (up to N99%) and moderate
enantioselectivity (up to 75% ee) [24]. Recently, we have developed a
new type of carbohydrate-derived prolinamide organocatalyst, which
is capable of catalyzing asymmetric aldol reaction, and a remarkably
better catalytic performance was provided by the reactions in terms
of productivity (up to 98%), diastereoselectivity (anti/syn 99:1) and
enantioselectivity (up to 99%) in water [25]. Independently and almost
simultaneously, Pedatella and coworkers [26]reported a new synthetic
catalyst, which were prepared by O-TBDPS D-glucosamine coupled
with L-proline, acting as an efficient organocatalyst in the accomplish-
ment of direct aldol reactions. Good chemical yields, as well as
☆
This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-No Derivative Works License, which permits non-
commercial use, distribution, and reproduction in any medium, provided the original
author and source are credited.
⁎
Corresponding author. Tel./fax: +86 571 28862867.
E-mail address: chxyzpf@hotmail.com (P. Zhang).
1566-7367/$ – see front matter © 2013 The Authors. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2013.07.011

C. Shen et al. / Catalysis Communications 41 (2013) 106–109
107
diastereomeric and enantiomeric ratios, were reported for the catalyzed
additions of cyclohexanone and acetone to variously substituted
benzaldehydes [27].
As part of our continued interest in the development of new
organocatalysts [24,25], herein we would like to introduce a new kind
of organocatalysts that combined carbohydrate with prolinamide to
be as a new organocatalysts and the study of its application in aldol
reaction between cyclohexanone and substituted benzaldehydes.
reduced pressure to give the crude product. For the deprotection of
the Fmoc-protected prolinamide derivative, piperidine (0.56 mL,
5.64 mmol) was added to a 0 °C solution of mixture (1.56 mmol)
in CH3CN (30 mL). The resulting mixture was maintained at 0 °C
for 30 min and at room temperature for 3 h, and the reaction was
continually monitored by TLC analysis then concentrated. The residue
was further purified by column chromatography on silica gel to give
final organocatalyst 4.
2. Experimental
2.4. Procedure for the synthesis of organocatalyst 5
2.1. Materials and methods
Piperidine (0.56 mL, 5.64 mmol) was added to a 0 °C solution of
Fmoc 4 (2.82 mmol) in CH3CN (30 mL). The resulting mixture was
maintained at 0 °C for 30 min and at room temperature for 3 h and
then concentrated. The crude residue was purified by recrystalliza-
tion from EtOH to give pure white solid 5.
Solvents were commercially obtained at the highest commercial
quality and were used without further purification. Column chromatog-
raphy was performed on silica gel grade 60 (230–400 mesh) (Analytical
TLC: Silica Gel 60, F254 plates from Merck, which were visualized by UV
and phosphomolybdic acid staining). Optical rotation values were
measured on a PerkinElmer P241 polarimeter. Enantiomeric excesses
(% ee) were determined by HPLC (Lab Alliance Model 500) analysis
using Chiralcel OJ-H, OD or AS-H column. The 1H and 13C NMR spectra
were recorded on a Bruker Avance DRX-400 spectrometer; chemical
shift, multiplicity (s = single, d = doublet, t = triplet, q = quartet,
br =broad, m = multiplet) are given in parts per million and are
referenced to residual solvent peaks (1H NMR and 13C NMR). Elemental
analyses were performed on Carlo-Erba 1106.
2.5. Procedure for the synthesis of organocatalyst 6
Compound 5 (1 mmol) was dissolved in 10 mL 5 N NaOCH3/
CH3OH solution and the reaction was monitored by TLC (10:1 ethyl
acetate/CH3OH). Upon completion, 2 N HCl was added until the solu-
tion was at neutral pH and was filtered. The solution was concentrat-
ed in vacuo and purified by flash chromatography 10:1 ethyl acetate/
CH3OH to give white product.
2.6. Representative procedure for the organocatalytic asymmetric aldol
reaction
2.2. Procedure for the synthesis of compound 1–3
The synthesis of compounds 1–3 was carried out according to the
literature procedure and our previous work [28,29].
The organocatalyst (0.005 mmol), cyclohexanone (0.105 ml,
1 mmol) and benzoic acid (2.4 mg, 0.02 mmol) was stirred in
1.0 mL of DMSO water for 20 min at 0 °C. Then aromatic aldehydes
(0.1 mmol) was added and the mixture was stirred for a specified re-
action time period. The mixture was treated with 10 mL of saturated
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was dried (MgSO4), filtered and concentrated to give
pure aldol adduct through flash column chromatography on silica
gel (hexane/ethyl acetate (3:1)). All the aldol products in the paper
are known compounds that exhibited spectroscopic data identical to
those reported in the literature. The anti:syn ratio was determined
by 400 MHz 1H NMR. The anti ee was determined by HPLC on chiral
2.3. Procedure for the synthesis of compound 4
Firstly, to a stirred solution of 20 mL THF, 0.31 mL Et3N and
0.674 g (2 mmol) N-(9H-fluoren-9-yl)methoxy)carbony-L-proline,
0.21 mL ethyl carbonochloridate was added to at 0 °C, the reaction
mixture was stirred at 0 °C for 30 minutes and compound 3 (2 mmol)
was added then stirred at room temperature for 16 h and heated at
reflux for 3 h, the reaction was continually monitored by TLC analysis.
At the end of the reaction, the organic phase was evaporated under
Scheme 1. Synthesis of novel carbohydrate-derived organocatalysts 5–6.

108
C. Shen et al. / Catalysis Communications 41 (2013) 106–109
column (Daicel, Chiralpak, OD or AD). All the experiments were
duplicated.
3. Results and discussion
With these organocatalysts in hand (Scheme 1), we then exam-
ined their efficiency in enantioselective aldol reaction with
4-nitrobenzaldehyde (7a) and cyclohexanone (8) as the model sub-
strates. Initially, we screened the new catalysts in catalyzing the direct
aldol reaction, respectively, in water with acidic additive at room tem-
perature for 12 h, and the results were summarized in Table 1.
We can find that 10 mol% of catalyst 5 show activity with good ee
and moderate yield (Table 1, entry 1). Good yield and moderate ee
value was reached when catalyst 6 was adopted (Table 1. entry 2).
Then optimization of the reaction conditions focusing on the effect of
the solvent (Table 1, entries 3–8) revealed that the mixture of (1:1)
(DMSO/water) is the best solvent leading to the quantitative conversion
of the substrate in a shorter time and afforded the product with 96%
yield and 90% ee (Table 1, entry 8).
Fig. 1. Optimization catalyst loading for the aldol reaction.a
We further examined the effect of temperature for the aldolization
of cyclohexanone through use of catalyst 5. The best result was obtained
by decreasing the reaction temperature to 0 °C (Table 1, entry 9). When
decreasing the reaction temperature to −25 °C, product 9a was
obtained with 92% ee, but the reaction was sluggish (Table 1, entry
10). Based on this cognition, we take 0 °C as the best temperature in
this reactions.
Further, we varied catalyst loading to see its influence on the reac-
tion. When the catalyst loading was varied, we can find that it did really
influence the rate and the ee value of the reaction (Fig. 1). For example,
when the reaction was performed by using 30 mol% organocatalyst 5,
the reaction was completed in good yield but with low ee value. How-
ever, when less catalyst was involved, for example 5 mol%, a lower
yield but higher ee value was obtained. Likewise, if less catalyst was
taken, for example, 1 mol% or 0.1 mol%, both the yield and the ee values
would be decreased. Based on the results in Fig. 1, we chose catalyst 5 at
5 mol % loading for further study.
aldehydes was further investigated. The nitro, chloro and cyano substit-
uents were chosen as electron-withdrawing groups, and the methoxy
and methyl substituent as a representative electron-donating group. As
shown in Table 2, the aldehydes substituted by a nitro group at the
ortho- and meta-position gave good yields of the corresponding aldol
products with 96% ee and 96% ee (Table 2, entries 2–3). Similarly, chloro
and cyano substituents proceed smoothly in excellent enantioselectivities
to furnish the aldol adducts 9d and 9e (Table 2, entries 3–4). The reaction
of less reactive benzaldehyde 7h, 7i and 7i with cyclohexanone also gave
products with 90% ee, 88% ee and 91% ee, respectively (Table 2, entries
6–8). The reaction between acetone and 4-nitrobenzaldehyde was also
carried out in the presence of catalyst 5. However, the asymmetric induc-
tion was not impressive. The reaction was performed at 0 °C to produce
the aldol product in 52% ee only.
In conclusion, we have reported the novel synthesis of carbohydrate-
derived prolinamide organocatalysts, which is capable of catalyzing
asymmetric aldol reaction. We screened out the catalyst, solvent,
temperature and catalyst loading. The products of the reaction between
cyclohexanone and aromatic aldehydes were obtained in high
yields (up to 99%) with excellent diastereo (up to N98:2 dr)- and
enantioselectivities (up to 97% ee). Further investigations on the
application of this kind of organocatalysts in asymmetric catalysis are
still under way in our laboratory.
With the optimized reaction parameters in hand, the substrate scope
of enantioselective aldol reaction of cyclohexanone with other aromatic
Table 1
Optimization condition for the aldol reaction.a
Table 2
Catalytic asymmetric aldol reactions of cyclohexanone with aromatic aldehydes.a
Entry Catalyst Solvent
T (°C) Time (h) Yield (%)b Anti/sync ee (%)c
1
2
3
4
5
6
7
8
5
6
5
5
5
5
5
5
5
5
5
6
H2O
H2O
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
12
24
24
24
65
82
72
96
90
92
93
96
97
51
81
86
95:5
85:15
90:10
92:8
93:7
88:12
95:5
94:6
98:2
96:4
92:8
95:5
85
76
83
81
79
82
88
Brine
neat
PhCH3
CH2Cl2
DMSO
DMSO/H2O rt
DMSO/H2O
DMSO/H2O −25
DMSO/H2O
DMSO/H2O
Entry
Ar+
Time (h)
Yield (%)b
Anti/sync
ee (%)c
1
2
3
4
5
6
7
8
3-NO2C6H4 (b)
2-NO2C6H4 (c)
4-CNC6H4 (d)
4-ClC6H4 (e)
Ph (f)
4-MeOC6H4 (g)
3-MeC6H4 (h)
2-MeOC6H4 (i)
24
24
24
24
24
48
48
48
99
96
90
95
86
87
82
86
95:5
97:3
97:3
92:8
91:9
95:5
93:7
96:4
96
97
95
97
96
90
88
91
90d
93d
92d
84d,e
9
0
10
11
12
0
0
d
77
a
Reaction conditions: 0.1 mmol of 7a, 1.0 mmol of 8, 10 mol% 5 or 6 and 10 mol%
benzoic acid was added as additive.
b
a
Isolated yields.
Determined by HPLC on a chiral column.
The mixture of (1:1)(DMSO/water) was employed as a solvent.
Without benzoic acid.
Reaction conditions: 0.1 mmol of 7, 1.0 mmol of 8, 5 mol% 5 and 10 mol% benzoic
c
acid in 1.0 mL of DMSO/water at 0 °C.
d
b
Isolated yields.
Determined by HPLC on a chiral column.
e
c

C. Shen et al. / Catalysis Communications 41 (2013) 106–109
109
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Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
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