New simple and recyclable O-acylation serine derivatives as highly enantioselective catalysts for the large-scale asymmetric direct aldol reactions in the presence of water

Article abstract of DOI:10.1016/j.tet.2011.03.083

New classes of O-acylation serine derived organocatalysts have been synthesized one-step by rational combination of serine with acyl chlorides at room temperature in trifluoroacetic acid. No protecting groups or chromatographic techniques are involved in

Full text of DOI:10.1016/j.tet.2011.03.083

Tetrahedron 67 (2011) 4283e4290
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New simple and recyclable O-acylation serine derivatives as highly
enantioselective catalysts for the large-scale asymmetric direct aldol reactions
in the presence of water
,
b
,
,
b,
c
,
a,b,c
Chuanlong Wu a c, Xiangkai Fu a
, Shi Li
*
a College of Chemistry and Chemical Engineering Southwest University, Research Institute of Applied Chemistry Southwest University, Chongqing 400715, China
b Key Laboratory of Applied Chemistry of Chongqing Municipality, Chongqing 400715, China
c Key Laboratory of Eco-environments in Three Gorges Reservoir Region Ministry of Education, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
New classes of O-acylation serine derived organocatalysts have been synthesized one-step by rational
combination of serine with acyl chlorides at room temperature in trifluoroacetic acid. No protecting
groups or chromatographic techniques are involved in any of the procedures, and certain combined
serine-surfactant organocatalysts mediate the direct aldol reactions of ketones with a series of aromatic
aldehydes to provide the aldol products in high yields (up to 99%) and enantioselectivities (up to 99% ee).
The catalyst 1b can be easily recovered and reused, and without significant decrease of enantioselectivity
was observed for five cycles. This novel catalyst can be efficiently used in large-scale reactions with the
enantioselectivities being maintained at the same level, which offers a great possibility for application in
industry.
Received 8 November 2010
Received in revised form 26 February 2011
Accepted 25 March 2011
Available online 31 March 2011
Keywords:
O-Acylation serine
Aldol reactions
Recyclable
Asymmetric catalysis
Organocatalysis
Large-scale
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
majority of organocatalytic reactions would yield racemic products
if the reactions took place in the presence of water.5f,g Recently, it
Asymmetric organocatalysis has become an important area of
research in organic synthesis.1 The asymmetric aldol reaction is one
of the most powerful methods for constructing carbonecarbon
bonds in chiral organic synthesis.2 A wide range of small organic
molecules, including proline3 and various other chiral pyrrolidine
derivatives,4 have been shown to be efficient catalysts for asym-
metric aldol reactions. Hayashi and Cordova demonstrated that
acyclic amino acids could effect direct aldol reactions in DMSO (in
the presence of a little water).5aef However, their shortcomings have
also been realized. One of the major limitations using these amino
acids or amino acids surrogates catalyzed aldol reactions was
employed in polar solvents, such as DMF, DMSO,5aef and NMP5g
owing to the solubility, while these high boiling point polar sol-
vents were often created added hurdles for product isolation and
environment pollution. Therefore, water had many attractive
advantages, such as low cost, safety, and environmentally benign
nature. We believe that the development of small organic molecules
capable of catalyzing enantioselective reactions using water as re-
action medium is attracting great interest. However, the vast
was shown by the groups of Takabe, Barbas, Hayashi, and Noto that
the direct asymmetric aldol reaction and the Michael reaction could
be catalyzed by the proline-derived hydrophobic catalysts in the
presence of water.6 Our group recently also reported the 4-phenoxy
substituted and 4-tertbutyldimethylsiloxy-substituted prolina-
mides catalyzed the direct aldol reactions between cyclic ketones
and aromatic aldehydes in the presence of water and reported the
O-acylation threonine derivatives catalyzed the direct aldol re-
actions and direct anti-mannich reactions.7 The groups of Teo and Lu
reported that the siloxy serine derivatives are highly efficient orga-
nocatalysts for asymmetric aldol reactions of ketones in the pres-
ence of water and in ionic liquid.8 Although serine was not efficient
organocatalysts in direct aldol reactions between cyclohexanone
and benzaldehyde in the presence of water,8a their hydrophobic
derivatives (e.g., O-TBDPSeserine) proved to be very efficient cata-
lysts. The desired aldol products were obtained in excellent yields
(up to 95%), and with nearly perfect enantiomeric control (up to 98%
ee).8 From a green chemistry point of view such studies are in-
teresting because the direct aldol reactions are atomicallyeconomic,
and water as the reactions medium is environment friendly.
Meanwhile, it is found that a subtle change in catalyst structure may
effect the catalytic activation. However, it should be noted that
* Corresponding author. Tel.: þ86 23 6825 3704; fax: þ86 23 6825 4000; e-mail
address: fxk@swu.edu.cn (X. Fu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.083

4284
C. Wu et al. / Tetrahedron 67 (2011) 4283e4290
among all of the reported asymmetric organocatalysts, most of them
were prepared with strenuous procedure, tiresome purification of
chromatography and/or need some expensive reagents,9 this will
also raise a cost concern when large amounts of these chiral orga-
nocatalysts are used for a large-scale synthesis in industrial appli-
cations, so these organocatalysts were often used in research
laboratories. Therefore, the development of novel, simple and highly
effective asymmetric organocatalysts with natural crude chiral pool,
simple preparation procedure, and inexpensive reagents is urgently
needed and is also the true challenge. An alternative strategy is to
design recyclable and subsequently reusable organocatalysts.
Meanwhile efforts also have been made on organocatalyst recycling
using polymer supports,10 ionic liquid supports,11 and fluorous
chemistry.12 In this context, we started a research project in order to
find new organocatalysts, structurally simple, recoverable and re-
usable, which are able to catalyze the asymmetric aldol reaction in
the presence of water, and these new organocatalysts can be used in
large-scale reactions with the enantioselectivities being maintained
at the same level.
Serine derivatives have been popularly designed to improve the
catalytic activity and stereoselectivity. The groups of Lu and Teo
reported siloxy serine derivative organocatalysts for the direct
asymmetric aldol reactions of various aromatic aldehydes and ke-
tone, and impressive results were obtained.8 We hypothesized and
deduced that incorporation of a simple and cheap aryl group into
a natural amino acid could generate a simple, cheap, and highly
enantioselective hydrophobic organocatalyst, which may interact
favorably with organic substrates in aqueous media due to its hy-
drophobic nature.13 Serine seems to be good chiral structural scaf-
folds, as the hydroxy group allows for the easy attachment of various
hydrophobic groups, such as alkyl, aryl, and so on.8 With the aim to
discover new simple and cheap organocatalysts for the direct
asymmetric aldol reaction in the presence of water, we prepared
eight new serine derivatives 1aeh. The R groups were varied in such
awaytoobtain molecules with increased hydrophobicitygoing from
the n-butyl to 3-phenylpropanoyloxy substituent (Fig. 1).
were screened as catalysts. As can be seen from the summarized
results in Table 1, natural serine as well as other hydrophilic amino
acids, such as proline, threonine, valine, leucine, and isoleucine was
not efficient organocatalyst in the presence of water (Table 1, entry
1),8a probably because they are dissolved in the water phase and
therebyseparated fromthe hydrophobic reactants of cyclohexanone
and 4-nitrobenzaldehyde.15 Under the same conditions, the cata-
lysts 1aeh with equivalent triethylamine can catalyze the asym-
metric direct aldol reaction of 4-nitrobenzaldehyde and
cyclohexanone to give the product in good yields (84e95%) with
different ee values (65e98% ee for anti-isomer) in the presence of
water (Table 1, entries 2e9). Among the eight O-acylation serine
derivatives, it was found that the chain length (n) dramatically
affected the yields and enantioselectivities (Table 1, entries 2e6).
Neither verylong(n¼6, 8,14) nor veryshort carbonchains (n¼2) was
effective, whereas catalyst 1b containing the n-hexanoyl group
(n¼4) gave the best yield (95%) and enantioselectivity (98% ee for
anti-isomer), but among the 1f,g, the chain length did not signifi-
cantly affected the yields, diastereoselectivities and enantiose-
lectivities (Table 1, entries 7e9). The serine derivative
organocatalyst 1b turned out to be the most efficient catalyst (Table
1, entry 3). These catalyzed process generated 1 equiv of triethyl-
amine HCl salt, which was not removed from the catalyst system. In
order to test the effect of triethylamine HCl salt on the aldol reaction
in the presence of water, we used the triethylamine HCl salt as
organocatalyst catalyzed the direct aldol reaction of cyclohexanone
Table 1
Screening of organocatalystsa
O
O
OH
O
Catalyst 1 (10 mol%)
+
H
Et3N (10 mol%)
NO2
NO2
H2O, r.t.
Entry
Catalyst
-Ser
1a
1b
1c
1d
1e
1f
Catalyst
loading (%)
Time (h)
Yieldb (%)
anti/sync
eec (%)
18a
2
3
4
5
6
7
8
9
L
10
10
10
10
10
10
10
10
10
10
48
20
20
20
20
20
20
20
20
72
e
e
e
Compounds 1aeh were easily prepared from serine with acyl
chlorides on the large-scale at room temperature in trifluoroacetic
acid in one-step. Furthermore, in the course of synthetic process, no
protecting groups or chromatographic techniques were involved
(Fig. 1).7d,e,f,14
90
95
94
90
84
90
92
93
e
64/36
94/6
70/30
72/28
87/13
80/20
83/17
84/16
e
65
98
91
92
68
73
76
76
e
1g
1h
Et3N$HCl
2. Results and discussion
10
a
The reactions were performed with 4-nitrobenzaldehyde (1 mmol), cyclohex-
anone (4 mmol), catalyst (0.1 mmol, see Table 1, entries 2e9), and Et3N (0.1 mmol,
see Table 1, entries 2e9) in the presence of water (0.2 mL) at room temperature.
The organocatalyzed aldol reaction was carried out using cyclo-
hexanone and 4-nitrobenzaldehyde as a model reaction to in-
vestigate different parameters, such as the catalysts, the
stoichiometry of reactants, loading of the catalysts, and the amount
of water. In our initial investigation serine and its derivatives 1aeh
b
Isolated yield.
Determined by chiral HPLC analysis (AD-H).
c
NH3Cl
1.Acyl chlorides(1.5 equiv)
NH2
CO2H
R
O
CF3CO2H
CO2H
HO
O
2.Crystallization from Et2O
1a n=2
1f
1b n=4
1c n=6
1d n=8
1e n=14
R=
R=
R=
n
R=
1g
1h
Fig. 1. O-Acyl derivatives of serine by selective O-acylation.

C. Wu et al. / Tetrahedron 67 (2011) 4283e4290
4285
and 4-nitrobenzaldehyde in the presence of water. Triethylamine
HCl salt was not an efficient organocatalyst in the presence of water
(Table 1, entry 10). So the triethylamine HCl salt did not affect the
yield, diastereoselectivity, and enantioselectivity.
Noticeably, using 10 mol % of catalyst 1b after 20 h, we obtained an
almost good yield and excellent stereoselectivity.
Some aldol reactions have been performed under aqueous
conditions, with the presence of water reported to increase the
reactivity and stereoselectivity.6,15b Using catalyst 1b (10 mol %)
with equivalent Et3N (10 mol %) we investigated the effect of dif-
ferent amount of water (Table 4). When in the presence of only
1 equiv of water (Table 4, entry 1), the aldol product was obtained
in a good yield with good diastereo- and excellent enantiose-
lectivity. However, using 5 or more equivalents of water (Table 4,
entries 2e4) a highly yield was observed. In each case stereo-
selectivities were high but, when a large amount of water
(17 equiv) was employed, we also obtained excellent diastereo- and
enantioselectivity, but the yield was decreased.
As a first step, we screened several solvents for the reaction
between cyclohexanone and 4-nitrobenzaldehyde (Table 2). Due to
its poor solubility in most such solvents, reactions mediated by serine
itself are restricted to polar organic solvents, such as dimethyl sulf-
oxide (DMSO), N,N-dimethylformamide (DMF), and N-methyl-
pyrrolidone (NMP), while O-acylation serine derived organocatalysts
are more soluble than serine in organic solvents. As catalyst we used
the most hydrophobic one (1b, 10 mol %). Both enantioselectivities
andyieldswerenotgoodwhentolueneandDMSOwereused(Table 2,
entries 1 and 2). Chloroform showed increased yield and enantiose-
lectivity (Table 2, entry 3), while water gave the highest stereo-
selectivity (Table 2, entry 4). This result indicates that water is
indispensable for achieving excellent diastereoselectivity and enan-
tioselectivity. Even brine showed a similar behavior (Table 2, entry 5).
When the direct aldol reactionwas carried out under neat conditions,
low diastereoselectivity was observed coupled with a decreased
enantioselectivity (Table 2, entry 6). The results summarized in Table
2 suggest that the reaction in the presence of water is different from
that in its absence, and that compared to organic solvents, water has
a unique beneficial effect.
Table 4
Effect of the amount of water in aldol reaction between cyclohexanone and 4-ni-
trobenzaldehydes catalyzed by 1ba
O
O
OH
O
Catalyst 1b (10 mol%)
Et3N (10 mol%)
+
H
NO2
H2O, 20 h, r.t.
NO2
Entry
H2O (mL)
Yieldb (%)
anti/sync
eec (%)
1
2
3
4
5
0.018
0.05
0.1
0.2
0.3
99
97
95
95
86
85/15
90/10
92/8
94/6
93/7
95
96
96
98
97
Table 2
Effect of the solvent on the catalytic aldol reaction between cyclohexanone and
4-nitrobenzaldehydes catalyzed by 1ba
O
O
OH
O
Catalyst 1b (10 mol%)
Et3N (10 mol%)
a
The reactions were performed with 4-nitrobenzaldehyde (1 mmol), cyclohex-
anone (4 mmol), catalyst 1b (0.1 mmol), and Et3N (0.1 mmol) in the presence of
water (see Table) at room temperature.
+
H
NO2
Solvent, 20 h, r.t.
NO2
b
Isolated yield.
Determined by chiral HPLC analysis (AD-H).
c
Entry
Solvent
Yieldb (%)
anti/sync
eec (%)
1
2
3
4
5
6
Toluene
DMSO
CHCl3
H2O
Brine
None
75
73
86
95
97
98
82/18
80/20
87/13
94/6
90/10
88/12
74
68
91
98
94
90
We also investigated the affects of ketone loading on the re-
action of 4-nitobenzaldehyde and cyclohexanone. When 10 mol %
of 1b with equivalent Et3N (10 mol %) was used, the reaction could
be accelerated by increasing the amount of ketone from 1 to
8 equiv, but dr and ee values were not improved (Table 5, entries
1e4), even with only 1 equiv of cyclohexanone. The aldol product
could be obtained in high yield with good stereoselectivity even
with only 4 equiv of cyclohexanone.
a
The reactions were performed with 4-nitrobenzaldehyde (1 mmol), cyclohex-
anone (4 mmol), catalyst 1b (0.1 mmol), and Et3N (0.1 mmol) in solvent (0.2 mL, see
Table) at room temperature.
b
Isolated yield.
Determined by chiral HPLC analysis (AD-H).
c
Table 5
Effect of the amount of cyclohexanone in aldol reaction between cyclohexanone and
Then, using water as reaction medium, we investigated the
above reaction employing different amounts of catalyst 1b with
equivalent Et3N (Table 3). Using a larger amount (15e20 mol %) of
catalyst, the reaction was faster but stereoselectivity was lower
than in the other cases. The amount was decreased up to 5 mol %.
After 20 h the yield was not good but dr and ee values were high.
4-nitrobenzaldehydes catalyzed by 1ba
O
O
OH
O
Catalyst 1b (10 mol%)
Et3N (10 mol%)
+
H
NO2
H2O, 20 h, r.t.
NO2
Entry
Cyclohexanone (equiv)
Yieldb (%)
anti/sync
eec (%)
Table 3
Effect of the amount of the catalyst in the aldol reaction between cyclohexanone and
1
2
3
4
1
2
4
8
84
93
95
96
91/9
93/7
94/6
92/8
95
96
98
97
4-nitrobenzaldehyde catalyzed by 1ba
O
O
OH
O
Catalyst 1b (X mol%)
+
H
Et3N (X mol%)
a
The reactions were performed with 4-nitrobenzaldehyde (1 mmol), cyclohex-
anone (see Table), catalyst 1b (0.1 mmol), and Et3N (0.1 mmol) in the presence of
water (0.2 mL) at room temperature.
NO2
NO2
H2O, r.t.
Yieldb (%)
anti/sync
eec (%)
b
Entry
Catalyst (mol %)
Time (h)
Isolated yield.
Determined by chiral HPLC analysis (AD-H).
c
1
2
3
4
20
15
10
5
12
12
20
20
99
98
95
78
84/16
85/15
94/6
76
80
98
96
In order to test the substrate generality of this organocatalyzed
direct aldol reaction, the reactionsof various aromatic aldehydes with
cyclohexanone were studied under the optimized conditions. The
results are summarized in Table 6. It can be seen that a wide range of
aromatic aldehydes can effectively participate in the aldol reactions.
From Table 6, we were able to access aldol adducts 2e18 derived from
93/7
a
The reactions were performed with 4-nitrobenzaldehyde (1 mmol), cyclohex-
anone (4 mmol), catalyst 1b (see Table), and Et3N (see Table) in the presence of
water (0.2 mL) at room temperature.
b
Isolated yield.
Determined by chiral HPLC analysis (AD-H).
c

4286
C. Wu et al. / Tetrahedron 67 (2011) 4283e4290
Table 6
Table 7
Organocatalyst 1b-catalyzed direct aldol reactions in the presence of watera
The direct aldol reactions of cyclopentanone with aromatic aldehydes catalyzed by
1ba
O
Catalyst 1b (10 mol%)
O
OH
O
O
Catalyst 1b (10 mol%)
O
OH
O
Et3N (10 mol%)
+
Et3N (10 mol%)
R
H
R
+
R
R
H2O, r.t.
H2O, r.t.
Yieldb (%)
anti/sync
eec (%)
Entry Product
Time (h) Yieldb (%) anti/sync eec (%)
Entry
Product
Time (h)
1
2
3
4
5
6
7
8
2(R¼p-NO2eC6H4)
3(R¼o-NO2eC6H4)
4(R¼m-NO2eC6H4)
20
20
20
95
97
98
96
95
89
83
89
96
89
68
56
60
67
75
68
90
94/6
97/3
96/4
99/1
92/8
84/16
94/6
94/6
97/3
92/8
98/2
87/13
90/10
90/10
97/3
95/5
90/10
98
99
96
96
95
96
96
95
97
96
98
94
>99
96
97
93
98
1
2
3
4
5
6
7
8
9
19(R¼p-NO2eC6H4)
20(R¼o-NO2eC6H4)
21(R¼m-NO2eC6H4)
22(R¼p-CF3eC6H4)
23(R¼p-BreC6H4)
24(R¼p-CleC6H4)
25(R¼o-CleC6H4)
26(R¼m-MeOeC6H4)
27(R¼2-Naphthyl)
28(R¼C6H4)
20
20
20
20
30
30
30
36
36
48
98
96
97
96
86
86
82
75
70
65
70/30
76/24
74/26
83/17
84/16
67/33
75/25
73/27
76/24
75/25
91/57
99/81
99/31
99/90
95/85
98/82
99/95
90/16
95/37
95/81
5(R¼2,4-Dinitrophenyl) 20
6(R¼p-CNeC6H4)
7(R¼p-CF3eC6H4)
8(R¼p-CleC6H4)
9(R¼o-CleC6H4)
10(R¼p-BreC6H4)
11(R¼p-FeC6H4)
12(R¼p-MeOeC6H4)
13(R¼m-MeOeC6H4)
14(R¼p-MeeC6H4)
15(R¼2-Naphthyl)
16(R¼1-Naphthyl)
17(R¼C6H4)
20
20
30
30
30
30
36
36
36
36
36
48
24
9
10
11
12
13
14
15
16
17
10
a
The reactions were performed with aldehyde (1 mmol), cyclopentanone
(4 mmol), 1b (0.1 mmol), and Et3N (0.1 mmol) in the presence of water (0.2 mL) at
room temperature.
b
Isolated yield.
c
Determined by chiral HPLC analysis (AD-H, OD-H) and comparison of the re-
tention times with literature data.6e
18(R¼Pyridinthyl)
a
The reactions were performed with aldehyde (1 mmol), cyclohexanone
(4 mmol), 1b (0.1 mmol), and Et3N (0.1 mmol) in the presence of water (0.2 mL) at
room temperature.
Table 8
Direct asymmetric aldol reactions between ketones and aromatic aldehydes cata-
b
Isolated yield.
lyzed by 1b in the presence of watera
c
Determined by chiral HPLC analysis (AD-H, OD-H) and comparison of the re-
tention times with literature data.7
Catalyst 1b (10 mol%)
Et3N (10 mol%)
CHO
R3
O
O
OH
+
R1
R1
their corresponding aromatic aldehydes and cyclohexanone. In the
presence of 10 mol % of catalyst 1b with equivalent Et3N (10 mol %)
and the amount of water (0.2 mL), most reactions between cyclo-
hexanoneandvariousaromaticaldehydesaffordedthealdolproducts
in excellent yields and nearly perfect ee values in the presence of
water. In general, the reaction between cyclohexanone and aromatic
R3
H2O, r.t.
R2
R2
Entry
Product
Time Yieldb anti/sync eec
(h)
(%)
(%)
aldehydes bearing electron-withdrawing substituents furnished b-
O
OH
hydroxy carbonyl aldol products in excellent yields (83e98%) and
enantioselectivities (95e99% ee for anti-isomer) within 20e30 h, es-
pecially the p-nitrobenzaldehyde and o-nitrobenzaldehyde (Table 6,
entries 1 and 2, 94/6 to 97/3 anti/syn ratio and 98e99% ee for anti-
isomers) (Table 6, entries 1e10). In contrast, longer reaction times
(36 h) were required for aromatic aldehydes containing an electron-
donating group to give comparatively lower yields (56e68%), but
without decrease of enantioselectivities, especially the p-tolualde-
hyde (Table 6, entry 13, 90:10 anti/syn ratio and >99% ee)(Table 6,
entries 11e13). This can be explained in that electron-withdrawing
groups enhance the electrophilicity of carbonyl carbons in aldehydes,
which facilitates the reaction, while electron-donating groups lessen
the electrophilicity. Moreover, the direct aldol reaction of neutral al-
dehydes catalyzed by the serine derivative organocatalyst 1b also
afforded the aldol products in high enantioselectivities and diaster-
eoselectivities (Table 6, entries 14e17). All the reactions of cyclohex-
anonewith aromatic aldehydes provided the corresponding products
with excellent enantioselectivities (94 to >99% ee for anti-isomers)
and excellent diastereoselectivities(anti/syn 84/16 to 98/2) (Table 6,
entries 1e17).
1
36
77
e
18
29
NO2
H
O
O
2d
36
48
32
85
e
73
94
29
N
O2
O
OH
3
93/7
NO2
O
O
30
O
O
OH
When cyclopentanone was employed interesting results were
obtained (Table 7). In particular, a good yield of 65e98% with ex-
cellent enantioselectivities (90e99% for the anti-isomer) were re-
ceived, however, the diastereomeric ratio obtained was only 67/33
to 84/16 dr (anti/syn).
4
5
30
48
90
68
95/5
97
92
NO2
NO2
31
OH
We also checked the aldol reactions of other ketones (acetone,
4,4-(ethylenedioxy)cyclohexanone,
tetrahydro-4H-pyran-4-one,
85/15
4-methylcyclohexanone, cycloheptanone, and O-TBS-hydroxy-
acetone) withnitrobenzaldehydeusingcatalyst 1b (10 mol %)(Table 8).
Thereactionwith acetonewas carried out both in the presence and in
O
32

C. Wu et al. / Tetrahedron 67 (2011) 4283e4290
4287
Table 8 (continued )
Table 9
The recycling and reuse of catalyst 1ba
Entry
Product
Time Yieldb anti/sync eec
O
OH
O
O
(h)
(%)
(%)
Catalyst 1b (10 mol%)
H
+
O
OH NO2
H2O, r.t.
NO2
NO2
6
7
48
63
91/9
92
Run
Time (h)
Yieldb (%)
anti/sync
eec (%)
O
1
2
3
4
5
20
20
20
30
48
95
94
94
91
84
94/6
94/6
97/3
93/7
91/9
98
97
97
95
91
33
OH
O
O
a
48
24
66
95
52/48
16/84
91
The reactions were performed with 4-nitrobenzaldehyde (10 mmol), cyclo-
hexanone (40 mmol), catalyst 1b (1 mmol), and Et3N (1 mmol) in the presence of
water (2 mL) at room temperature.
NO2
NO2
b
34
OH
Isolated yield.
Determined by chiral HPLC analysis (AD-H).
c
8
97 (syn)
recovered catalyst 1b retained essentially its catalytic activity
without further purification. No significant decrease in the enan-
tioselectivity was observed over five cycles (Table 9).
OTBS
35
We further performed large-scale asymmetric aldol reactions
with 2 mol of aromatic aldehydes and 4 equiv of ketones using a 2 L
round-bottomed flask. The same catalyst loading of 10 mol % as in
the experimental scale was used. The large-scale experiments can
be facilely carried out using the same procedure as for the experi-
mental scale reactions. As can be seen from the results summarized
in Table 10, to our delightfully, the enantioselectivities maintained
at the same level for the large-scale reactions. So the serine de-
rivative organocatalyst 1b is not only simple, cheap, and prepared
easily (one-step) but also the enantioselectivities maintained at the
same level for the large-scale aldol reactions, which offers a great
possibility for applications in industry.
a
The reactions were performed with aldehyde (1 mmol), ketones (4 mmol), 1b
(0.1 mmol), and Et3N (0.1 mmol) in the presence of water (0.2 mL) at room
temperature.
b
Isolated yield.
c
Determined by chiral HPLC analysis (AD-H, OD-H and OJ-H) and comparison of
the retention times with literature data.6e,7,8
d
Carried out in neat.
the absence of water. In the first case we obtained the aldol product
in high yield (77%) and low enantioselectivity (18%) (Table 8, entry
1). Whenwe carried out the reactionwithout water (Table 8, entry 2)
we obtained the aldol product in low yield (32%) and good enan-
tioselectivity (73%). However, it is worth noting that the configura-
tion of aldol product was reversed. In our opinion the presence of
water increased the activity of the catalyst because the more hy-
drophilic medium increased the affinity of the hydrophobic alde-
hyde to the hydrophobic catalyst. When water was absent, the
aldehydewas welldissolvedinacetoneand this causedaloweryield.
More difficult to explain is the observed enantioselectivity in the
presence of water. By contrast, the reaction between cyclohexanone
and 4-nitrobenzaldehyde under neat conditions did not show a re-
versed enantioselectivity. This is probably due to the different hy-
drophilicity between the acetone and cyclohexanone. The 4,4-
(ethylenedioxy)cyclohexanone and 4-methylcyclohexanone gave
high stereoselectivities and good yield (Table 8, entries 3 and 4),
whereas excellent enantioselectivities were obtained using tetra-
hydro-4H-pyran-4-one and cycloheptanone both with catalysts 1b,
but lower yields and diastereoselectivities were obtained (Table 8,
entries 5e7). Protection of the free hydroxy function with the TBS
group furnished a hydrophobic substrate, which then efficiently
reacted with the aldehyde in aqua, which also gave high stereo-
selectivities and good yield (Table 8, entry 8).
Meanwhile, in order to verify that the serine derivative orga-
nocatalyst 1b could be recovered and reused, we performed
a recycling study of 1b using the aldol reaction between cyclo-
hexanone and 4-nitrobenzaldehyde (Table 9). The catalyst 1b could
be easily recovered from the reaction mixture after completion of
the reaction by acid treatment; the aldol product was extracted
with ethyl ether (Et2O), evaporation of the organic solution to ob-
tain the aldol product. The catalyst 1b exists in the acidic aqueous
layer, and then added an equivalent amount of triethylamine
(Et3N), and resulted white suspension. The suspension was filtered
under vacuum and the white crystals were used directly in sub-
sequent reaction cycles without adding any new catalyst. In each
reuse, the same amounts of substrates were used, and the
3. Conclusions
In conclusion, the results from the investigation demonstrate
that the O-acylation serine organocatalyst 1b is a robust and effec-
tive catalyst for highly enantioselective aldol reactions. Awide range
of aromatic aldehydes with cyclic and acyclic ketones can effectively
participate in the direct aldol reactions. The electronic effect of the
substituents in substituted benzaldehydes has been discussed.
Noteworthy features of this catalysis system are (1) the direct aldol
reactions proceeded in the presence of water using simple pro-
cedures; (2) O-acylation serine organocatalysts 1aeh can be pre-
pared easily (one-step) and economically from commercially
available sources, with both enantiomers readily available; (3)
10 mol % of catalyst 1b was sufficient to furnish the aldol products in
excellent yields (up to 99%) and enantioselectivities (up to 99%); (4)
The catalyst can be readily recovered and reused without significant
loss of catalytic activity and stereoselectivity; Notably, (5) this
organocatalyzed direct asymmetric aldol reaction can be performed
on a large-scale with the enantioselectivity being maintained at the
same level, which offers a great possibility for applications in
industry.
4. Experimental section
4.1. General remarks
All reagents were commercial products. The reactions were mon-
itored by TLC (thin layer chromatography). The column and pre-
parative TLC purificationwerecarriedoutusingsilicagel. Flashcolumn
chromatography was performed on silica gel (200e300 mesh). NMR
spectra were recorded on a 300 MHz instrument (Bruker Avance 300

4288
C. Wu et al. / Tetrahedron 67 (2011) 4283e4290
Table 10
spectrometer). Chemical shifts (d) are given in parts per million rela-
Large-scale asymmetric aldol reactionsa
tive toTMS as the internal reference, coupling constants (J) in Hertz. IR
spectra were recorded with a Bruker Tensor 27 FTIR spectrometer.
Melting points were measured on a digital melting point apparatus
(TAQ100). Mass spectra (MS) were measured with a Bruker HCT mass
spectrometer. Analytical high performance liquid chromatography
(HPLC) was carried out on Agilent 1200 instrument using Chiralpak
AD-H (4.6 mmꢀ250 mm), Chiralpak OJ-H (4.6 mmꢀ250 mm), and
Chiralcel OD-H (4.6 mmꢀ250 mm) columns. Optical rotations were
Catalyst 1b (10 mol%)
O
O
O
OH
Et3N (10 mol%)
H
+
R
R
H2O, r.t.
Entry
1
Product
Time (h) Yieldb (%) anti/sync eec (%)
O
OH
measured on a JASCO P-1010 Polarimeter at
l¼589 nm.
20
92
91/9
97
4.2. Typical experimental procedure for the preparation of
NO2
NO2
the O-acylation serine organocatalysts 1aeh14
O
OH
A 500 mL round bottom flask was charged with CF3CO2H
(120 mL) and placed in an ice/water bath. Powdered serine
(250 mmol, dried at 70e75 ꢁC for 24 h) was added in small portions
under vigorous stirring to give a viscous solution (leaving some
small pieces of undissolved material). The reaction mixture was
stirred for 15 min, and then removed from the ice/water bath. After
5 min of stirring, acyl chloride (375 mmol) was added in one por-
tion. The reaction flask was fitted with a loose glass stopper, and the
reaction mixture was stirred at room temperature without any
external temperature adjustment for 12 h, giving a clear and col-
orless solution. The reaction flask was then cooled in an ice/water
bath, and Et2O (360 mL) was added under vigorous stirring over
a period of 20 min, slowly at first. The resulting white suspension
was stirred at 0e5 ꢁC for 15 min after completed addition, and then
filtered by vacuum. The crystals were washed with two portions of
Et2O and dried at room temperature for 23 h in a ventilated hood to
give O-acylation serine hydrochloride 1aeh. This essentially pure
material was used for the next step without further purification.
2
3
20
30
96
85
94/6
92/8
95
95
O
OH
Cl
O
OH Cl
4
5
30
30
88
94
91/9
92/8
95
97
O
OH
Br
O
OH
4.2.1. (S)-O-(n-Butyl)-
50.79 g, yield: 96%, mp: 121e123 ꢁC; [
(KBr):
¼2969, 1742, 1622, 1557, 1463, 1256, 1176, 1100, 1046, 751,
594 cmꢂ1 1H NMR (300 MHz, DMSO)
¼0.82e0.87 (m, 3H),
L
-serine hydrochloride (1a). White solid;
20
6
7
36
36
60
67
93/7
94/6
97
95
a
]
D
þ17.2 (c 1, MeOH). IR
n
CH3
;
d
1.45e1.57 (m, 2H), 2.26e2.31 (m, 2H), 4.25 (dd, J¼6.4 Hz and 3.7 Hz,
O
OH
1H), 4.35 (m, 2H) ppm. 13C NMR (75.5 MHz, DMSO)
35.1, 51.3, 61.4, 168.3, 172.4 ppm. MS (ESI): 175.52.
d
¼13.5, 17.7,
OMe
4.2.2. (S)-O-(n-Hexanoyl)-
58.13 g, yield: 97%, mp: 125e127 ꢁC; [
(KBr):
¼2961, 2932, 1753, 1631,1598, 1463, 1256, 1176, 1100, 1046,
751, 594 cmꢂ1 1H NMR (300 MHz, D2O)
L
-serine hydrochloride (1b). White solid;
20
a]
þ14.3 (c 1, MeOH). IR
D
O
OH
n
8
9
48
20
66
94
95/5
92
91
;
d¼0.78e0.82 (m, 3H),
1.22e1.23 (m, 4H), 1.51e1.56 (m, 2H), 2.29e2.40 (m, 2H), 4.168 (dd,
J¼6.4 Hz and 3.6 Hz, 1H), 4.41(m, 2H) ppm. 13C NMR (75 MHz,
OH
OH
DMSO)
d
¼13.7, 21.2, 23.4, 30.0, 33.0, 33.4, 54.2, 61.4, 169.7,
O
175.7 ppm. MS (ESI): 203.52.
70/30
4.2.3. (S)-O-(n-Octanoyl)-
L
-serine hydrochloride (1c). White solid;
NO2
NO2
63.59 g, yield:95%, mp:128e129 ꢁC;[
a]
D
20 þ11.3(c 1, MeOH). IR(KBr):
n
¼2956, 2927, 2856, 1749, 1650,1598, 1463, 1256, 1163, 1100, 1046,
751, 594 cmꢂ1
;
1H NMR (300 MHz, DMSO):
d¼0.84e0.86 (m, 3H),
O
10
20
30
92
84
60/40
66/34
98
96
1.25 (br, 8H), 1.52 (m, 2H), 2.31e2.35 (m, 2H), 4.28 (dd, J¼6.4 Hz and
3.7 Hz, 1H), 4.36 (m, 2H). 13C NMR (75 MHz, DMSO):
¼14.0, 22.2,
24.2, 28.5, 31.2, 33.3, 51.3, 61.5, 168.4, 172.5 ppm. MS (ESI): 231.52.
d
OH
O
4.2.4. (S)-O-(n-Decanoyl)-
70.99 g, yield: 96%, mp: 128e130 ꢁC; [
(KBr):
¼2957, 2923, 2851, 1748, 1633, 1598, 1463, 1256, 1163, 1100,
1046, 751, 594 cmꢂ1; 1H NMR (300 MHz, CD3OD):
L
-serine hydrochloride (1d). White solid;
11
20
a
]
þ12.5 (c 1, MeOH). IR
D
n
Cl
d¼0.90e0.95 (m,
a
The reactions were performed with aldehyde (2 mol), ketone (4 equiv), catalyst 1b
(0.2 mol), and Et3N (0.2 mol) in the presence of water (400 mL) at room temperature.
3H), 1.33 (br, 12H), 1.62e1.67 (m, 2H), 2.41e2.45 (m, 2H), 4.40 (dd,
J¼6.3 Hz and 3.8 Hz, 1H), 4.56 (m, 2H) ppm. 13C NMR (75 MHz,
b
Isolated yield.
c
CD3OD):
d
¼14.5, 23.7, 25.7, 30.1, 30.2, 30.4, 30.5, 33.0, 24.5, 53.3,
Determined by chiral HPLC analysis (AD-H, OD-H).
62.6, 169.0, 174.4 ppm. MS (ESI): 259.56.

C. Wu et al. / Tetrahedron 67 (2011) 4283e4290
4289
4.2.5. (S)-O-(n-Palmitoyl)-
89.29 g, yield: 94%, mp: 130e131 ꢁC; [
(KBr):
¼2957, 2922, 2850, 1749, 1691, 1417, 1354, 1165, 1122, 1066,
750, 698 cmꢂ1 1H NMR (300 MHz, DMSO):
L
-serine hydrochloride (1e). White solid;
4.5. General procedure for large-scale aldol reactions
20
a]
þ10.6 (c 1, MeOH). IR
D
n
To a mixture of catalyst 1b (0.2 mol) with equivalent triethyl-
amine (0.2 mol), water (400 mL), and ketone (8 mol) were added
aromatic aldehyde (2 mol) using a 2 L round-bottomed flask. The
resulting mixture was stirred at room temperature. The reaction was
monitored by TLC. It was then quenched with 200 mL saturated
NH4Cl solution, extracted with EtOAc (3ꢀ500 mL), and dried over
Na2SO4. Purification by flash chromatography afforded the corre-
sponding pure products.
;
d
¼0.83e0.85 (m, 3H),
1.23 (br, 24H), 1.51 (br, 2H), 2.32 (t, J¼7.1 Hz, 2H), 4.29 (dd, J¼6.4 Hz
and 3.7 Hz, 1H), 4.45 (m, 2H) ppm. 13C NMR (75 MHz, DMSO):
d
¼14.0, 22.1, 24.1, 28.5, 28.8, 28.8, 29.0, 29.1, 31.3, 33.1, 51.2, 61.4,
168.3, 172.4 ppm. MS (ESI): 343.51.
4.2.6. (S)-O-(Benzoyloxy)-
55.27 g, yield: 90%, mp: 119e120 ꢁC; [
(KBr):
¼3500e2600, 1750, 1691, 1417, 1354, 1165, 1122, 1066, 750,
698 cmꢂ1 1H NMR (300 MHz, DMSO):
¼4.48 (dd, J¼6.4 Hz and
3.7 Hz, 1H), 4.81 (m, 2H), 7.55e7.58 (m, 2H), 7.68e7.73 (m, 1H),
8.08e8.10 (m, 2H) ppm. 13C NMR (75 MHz, DMSO):
¼51.4, 62.5,
128.7, 128.9, 129.8, 133.8, 165.2, 168.3 ppm. MS (ESI): 209.47.
L
-serine hydrochloride (1f). White solid;
20
a
]
ꢂ11.5 (c 1, MeOH). IR
D
Acknowledgements
n
;
d
All authors herein are grateful to the financial supports from
NationalMinistryof Science andTechnology InnovationFund for High-
tech Small and Medium Enterprise Technology (NO.09C26215112399).
And National Ministry of Human Resources and Social Security Start-
up Support Projects for Students Returned to Business, Office of
Human Resources, and Social Security Issued 2009 (143).
d
4.2.7. (S)-O-(2-Phenylacetoxy)-
solid; 59.07 g, yield: 91%, mp: 118e119 ꢁC; [
IR (KBr):
1066, 750, 699 cmꢂ1
J¼2.2 Hz, 2H), 4.31 (dd, J¼6.4 Hz and 3.7 Hz, 1H), 4.40 (m, 2H),
7.25e7.34 (m, 5H) ppm. 13C NMR (75 MHz, DMSO):
¼39.8, 51.4,
62.5, 128.7, 128.9, 129.8, 133.8, 165.2, 168.4 ppm. MS (ESI): 223.50.
L
-serine hydrochloride (1g). White
a
]
20 þ16.5 (c 1, MeOH).
D
n
¼3500e2600, 2850, 1748, 1691, 1417, 1354, 1165, 1122,
1H NMR (300 MHz, DMSO):
d¼3.83 (d,
Supplementary data
;
Complete experimental procedures are provided, including 1H
and 13C spectra, of all new compounds. Supplementary data asso-
ciated with this article can be found in online version at
doi:10.1016/j.tet.2011.03.083.
d
4.2.8. (S)-O-(3-Phenylpropanoyloxy)-
L
-serine hydrochloride (1h).
20
White solid; 64.17 g, yield: 94%, mp: 120e122 ꢁC; [
a]
D
þ15.5 (c 1,
References and notes
MeOH). IR (KBr):
n
¼3500e2600, 2850, 1755, 1691, 1417, 1354, 1165,
1122, 1066, 750, 720 cmꢂ1
;
1H NMR (300 MHz, CD3OD):
d¼2.75 (t,
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J¼7.6 Hz, 2H), 2.97 (t, J¼7.6 Hz, 2H), 4.37 (dd, J¼6.3 Hz and 3.6 Hz,1H),
4.55 (m, 2H), 7.19e7.32 (m, 5H) ppm. 13C NMR (75 MHz, CD3OD):
d
¼31.6, 36.3, 53.4, 62.8, 127.3, 129.3, 129.3, 129.5, 133.8, 141.7, 169.0,
173.6 ppm. MS (ESI): 237.49.
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amine (0.1 mmol), water (0.2 mL), andketone (4.0 mmol) were added
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molecules are distributed uniformly in the watereoil interface and
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EtOAc (3ꢀ5 mL), and dried over Na2SO4. Purification by flash chro-
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A Johnson Matthey

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