One-pot production of chiral α,β-epoxy ketones from benzaldehydes and acetophenones by recyclable poly(amino acid) catalysis

Article abstract of DOI:10.1016/j.tet.2011.05.024

An efficient one-pot, two-step process was disclosed for production of chiral α,β-epoxy ketones from benzaldehydes and acetophenones catalyzed by imidazolium-modified poly(l-leucine). Two effective reaction systems with complementary high enantioselectivities (up to 98% ee) or satisfactory yields (up to 89%) have been developed. Importantly, the poly(amino acid) catalyst can be easily recovered and recycled for ten times without losing its catalytic efficiency in terms of both enantioselectivity and yield.

Full text of DOI:10.1016/j.tet.2011.05.024

Tetrahedron 67 (2011) 5289e5292
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot production of chiral
a,b-epoxy ketones from benzaldehydes
and acetophenones by recyclable poly(amino acid) catalysis
,
c
,
a,b
Wanrong Luo a, Zhichao Yu a, Wenwei Qiu a, Fan Yang a , Xiaofeng Liu , Jie Tang
*
*
a Department of Chemistry, East China Normal University, Shanghai 200062, China
b Institute of Drug Discovery and Development, East China Normal University, Shanghai 200062, China
c Reata Pharmaceuticals Inc., 2801 Gateway Drive Suite 150, Irving, TX 75063, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot, two-step process was disclosed for production of chiral
benzaldehydes and acetophenones catalyzed by imidazolium-modified poly(
reaction systems with complementary high enantioselectivities (up to 98% ee) or satisfactory yields (up
to 89%) have been developed. Importantly, the poly(amino acid) catalyst can be easily recovered and
recycled for ten times without losing its catalytic efficiency in terms of both enantioselectivity and yield.
Ó 2011 Elsevier Ltd. All rights reserved.
a
,
b
-epoxy ketones from
Received 28 January 2011
Received in revised form 25 April 2011
Accepted 9 May 2011
L-leucine). Two effective
Available online 13 May 2011
Keywords:
One-pot
Condensation
Asymmetric epoxidation
Poly(L-leucine)
1. Introduction
industry. A variety of chiral catalytic systems have been developed
for this purpose to date3,15e17 and homo-oligopeptides were con-
Asymmetric epoxidation is a remarkably powerful organic
transformation, which can efficiently establish two stereogenic
centers in one simple operation. In the past several decades, a broad
spectrum of endeavors have been made to turn this fundamentally
important strategy into many synthetically useful asymmetric ep-
oxidation methods.1e13 However, no universal method is available
for highly enantioselective epoxidation of all classes of different
alkene structures. Continuously exploring more effective and
practical catalytic systems for asymmetric epoxidation of each
specific class of alkene structures is currently still of great interest
sidered as the most powerful chiral catalysts.17 However, almost all
the successful asymmetric syntheses of chiral epoxy ketones are
a two-step sequence: (1) synthesis of
a
,
b
-enones and (2) asym-
-enones. Few successful examples of one-
a,b-epoxy ketones directly from an aldehyde
metric epoxidation of
pot synthesis of chiral
a,b
and a ketone have been reported18,19 by using these existing cata-
lytic systems. The reason could be partially due to the deactivation
of the chiral catalyst when it is exposed to the reaction mixture in
the condensation reaction (first step). For instance, Choudary and
co-workers developed a bifunctional nonocrystalline MgO catalyst
for synthesizing chiral epoxy ketones. The synthesis began with the
condensation of benzaldehydes with acetophenones to yield chal-
cones followed by asymmetric epoxidation to afford chiral epoxy
ketones with moderate to good yields and moderate to high
enantioselectivities (ees) in a two-pot reaction.18 However, they
failed to develop a similar efficient one-pot reaction with the same
catalytic system and reasoned that as the poisoning effect of water,
which was formed in situ in the condensation reaction and adsor-
bed on the catalyst. In 2007, Liang and co-workers reported the first
example of a combination of condensation and epoxidation process
for the synthesis of chiral epoxy ketones with an expensive alka-
loid, Cinchona, as catalyst.19 However, the enantionselectivities
varied from moderate to high while the yields are generally just
moderate, furthermore, the expensive chiral catalyst may be diffi-
cult to isolate from the reaction system and to be reused. More
to organic chemists. Among a variety of olefin substrates,
a,b-
enones are particularly attractive since they can undergo the
asymmetric epoxidation to provide a class of versatile building
blocks, chiral epoxy ketones, with complementary reactivities of
epoxide and carbonyl functional groups. These chiral multi-
functionalized compounds have been extensively used in making
valuable bioactive molecules and natural products in both synthetic
organic laboratories and various chemical manufacturers, ranging
from pharmaceutical to agriculture industries.14 Therefore, de-
velopment of highly efficient and reliable asymmetric epoxidation
of a,b-enones has drawn great attention from both academia and
* Corresponding authors. Fax: þ86 21 62232100; e-mail addresses: fyang@
chem.ecnu.edu.cn (F. Yang), liu@reatapharma.com (X. Liu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.024

5290
W. Luo et al. / Tetrahedron 67 (2011) 5289e5292
recently, Shi and Dai reported a one-pot way to synthesize
a
,
b
-
reactions, such as Cannizzaro reaction of benzaldehyde and self-
condensation of acetophenone incurring under the strong basic
environment in the condensation reaction. Therefore, lower con-
centration of KOH aqueous solution was used to suppress these side
reactions in order to increase the overall yield, although a decrease
of reaction rate was observed. The optimal balance between se-
lectivity and reactivity was achieved by using 10% w/w KOH
aqueous solution as the CSC reaction solvent to afford the chiral
epoxychalcone in 96% ee and 75% overall yield (Table 1, entry 3 vs
entries 1 and 2). Change of the organic solvent for the asymmetric
epoxidation from toluene to CH2Cl2 slightly decreased the overall
yield although the enantioselectivity remained the same (Table 1,
entry 3 vs entry 4).
epoxy ketones oxidized by hydrogen peroxide in methanol, but it is
a non-chiral epoxidation process.20
Attracted by its simple experimental procedure and inexpensive
operational cost, we are particularly interested in developing
a novel one-pot synthesis of chiral a,b-epoxy ketones directly from
an aldehyde and a ketone with a recyclable catalyst. We envisaged
that these chiral compounds could be prepared by a Clai-
seneSchmidt condensation (CSC) followed by an asymmetric ep-
oxidation. The key element to ensure the successful development of
such a process with high enantioselectivity and good yield is the
employment of a proper chiral catalyst. In our previous research,
we discovered a new asymmetric catalyst, which could rapidly
ꢀ
catalyze JuliaeColonna epoxidation of chalcones within several
In order to examine the scope of this one-pot CSC-asymmetric
epoxidation chemistry, a variety of aromatic benzaldehydes and
acetophenones were subjected to the optimal reaction system. The
results are demonstrated in Table 2. Almost all of the aromatic al-
dehydes and acetophenones bearing substituents with various
electronic (both electronic rich and deficient) and steric properties
at different (meta- and para-) positions on the aromatic rings un-
derwent the one-pot CSC-asymmetric epoxidation smoothly to
afford the corresponding substituted chiral epoxychalcone in good
yields and excellent ees (Table 2, entries 1, 3e7, and 9e13). Only in
two cases, while o-methoxy benzaldehyde/acetophenone (74% ee,
Table 2, entry 2) and benzaldehyde/m-bromoacetophenone (80%
ee, Table 2, entry 8) were used as condensation partners, the
asymmetric epoxidation performed less selectively but still gave
the final products in good ees. The enantioselectivity for the oxi-
dation of chalcone was much higher than that of Liang’s catalytic
system (97% ee vs 87% ee).19
minutes to produce the corresponding chiral epoxychalcones in
satisfactory enantioselectivities and yields.21 More importantly the
modified poly(amino acid) catalyst could be quantitatively and
repeatedly recycled and reused in the next batch of reaction
without losing its catalytic activity. Herein, we wish to report
a convenient and efficient one-pot process for production of chiral
a,b-epoxy ketones directly from benzaldehydes and acetophenones
with the recyclable poly(amino acid) as catalyst for the first time
(Scheme 1).
O
1) KOH, Solvent
2) Percarbonate,
O
O
O
+
R1
R2
CH3
R2
H
R1
98%ee
89% yield
H
N
N
N
N
H
Table 2
Cl-
Synthesis of chiral epoxides with [3-apmim]Cl-PLL in heterogeneous solvent re-
H
O
action systema
30
O
1) 6 eq 10%KOH, H2O, RT
O
O
[3-apmim]Cl-PLL
O
+
R2
R1
2) 1.5 eq Percarbonate, 0.2 eq Cat,
R1
R2
Scheme 1.
Toluene/H2O, 0 o
C
Entry
R1
R2
Yield (%)
ee (%)
2. Results and discussion
1
2
3
Ph
Ph
Ph
75
55
68
67
68
72
74
64
62
66
74
76
75
97
74
97
96
90
90
90
80
98
96
96
95
96
o-MeOC6H4
m-MeOC6H4
p-ClC6H4
p-BrC6H4
m-BrC6H4
p-MeC6H4
Ph
Ph
Ph
Ph
Ph
PH
Ph
Ph
Ph
Ph
m-BrC6H4
p-BrC6H4
p-ClC6H4
We initiated our project with a ClaiseneSchmidt condensation
of benzaldehyde and acetophenone with 6 equiv of KOH in H2O,
followed by an asymmetric epoxidation in an added organic solvent
in the presence of sodium percarbonate (1.5 equiv) and catalytic
amount of [3-apmim]Cl-PLL (0.2 equiv). The CSC reaction with high
concentrated KOH aqueous solution proceeded quickly into com-
pletion followed by the asymmetric epoxidation to afford the chiral
epoxychalcone in 94% ee and 61% overall yield (Table 1, entry 1).
The moderate overall yield could be caused due to the side
4b
5b
6
7
8
9b
10
11
12
13b
m-MeC6H4
p-MeC6H4
p-MeOC6H4
Ph
a
Reaction conditions: aldehyde (1.0 mmol), ketone (1.0 mmol), KOH (6 mmol),
H2O (3 mL), rt; then percarbonate (1.5 mmol), [3-apmim]Cl-PLL (0.2 mmol), toluene
(3 mL), 0 ꢀC.
Table 1
Optimization of the reaction conditions in heterogeneous solvent reaction systema
b
Aqueous KOH (50%) was used.
O
O
O
O
1) KOH (6mmol), RT
+
2) 1.5 eq Percarbonate, 0.2 eq Cat,
As we demonstrated in our previous publication, the
imidazolium-modified PLL catalysts are generally powdery solids,
which are insoluble in either water or organic solvents. This im-
portant physical property plus their high catalytic efficiency make
the imidazolium-modified PLLs excellent candidate catalysts for
recycle and reuse in asymmetric epoxidation chemistry. Hence, we
investigated the reusability of [3-apmim]Cl-PLL catalyst used in this
research and the results are summarized in Table 3. According to
the experimental data, it clearly demonstrates that [3-apmim]Cl-
PLL catalyst is a valuable catalyst for this one-pot CSC-asymmetric
epoxidation since it can be almost quantitatively recycled and
Toluene/H2O, 0 o
C
Entry
KOH (%)
Solvent
Time (h)b
Yield (%)
ee (%)
1
2
3
4
50
20
10
10
Toluene
Toluene
Toluene
DCM
2(8)
61
69
75
70
94
95
96
96
24(12)
24(12)
24(12)
a
Reaction conditions: benzaldehyde (1.0 mmol), acetophenone (1.0 mmol), KOH
(6 mmol), H2O (3 mL), room temperature (rt) then percarbonate (1.5 mmol), [3-
apmim]Cl-PLL (0.2 mmol), solvent (3 mL), 0 ꢀC.
b
The value in parentheses is the epoxidation reaction time.

W. Luo et al. / Tetrahedron 67 (2011) 5289e5292
5291
successfully reused for 10 cycles without deterioration in catalytic
efficiency. Noteworthy, the recycle of this insoluble, powdery cat-
alyst can be easily achieved by a simple filtration after the reaction
has completed.
binary solvent mixture and equivalent of base (KOH) loading suc-
cessfully revealed the optimized reaction condition (Table 4, entry
10 vs entries 5e10). Generally, the stereoselectivity of the asym-
metric epoxidation is temperature dependence, and performing the
epoxidation reaction at lower temperature usually enhances the
enantioselectivity. Thus, 84% yield and 95% ee were achieved by
carrying out the reaction in THF/H2O (1:3) homogeneous binary
solvent system, and with 0.5 equiv KOH at 0 ꢀC (entry 11).
Table 3
PLL catalyst recycle and reusea
O
O
O
O
1) 10% KOH (6 eq.), RT, 24h
+
The generality of this alternative reaction system has been in-
vestigated and the results are shown in Table 5. A series of con-
densation partners bearing substituents with various electronic
(both electronic rich and deficient) and steric properties at different
(ortho-, meta-, and para-) positions on the aromatic rings were
subjected to this homogenous solvent reaction system and all
afforded the chiral epoxychalcones in satisfactory yields and good to
excellent ees. In general, the yields in this homogenous solvent re-
action system are significantly higher (up to 22% higher) than those
in the heterogeneous solvent one with no or slight enantiose-
lectivity decreasing (Table 5 vs Table 2). For the substrate benzal-
dehyde, p-chlorobenzaldehyde, and p-bromobenzaldehyde, the
yields were 20e30% higher than that of Shi’s method.20 One ex-
ception is noteworthy, the condensation partner para-bromo
benzaldehyde/acetophenone achieved both higher yield and ee
when the reaction was performed in this homogenous solvent re-
action system compared to the data from the heterogeneous solvent
one (83% yield and 93% ee, Table 5, entry 4 vs 68% yield and 90% ee,
Table 2, entry 5). According to these experimental results, we con-
cluded that these two reaction systems have complementary high
yields or enantioselectivities as their merits. Therefore, they both
should be considered as effective reaction systems for one-pot CSC-
asymmetric epoxidation chemistry in terms of high enantiose-
lectivities and satisfactory yields. Most importantly, both of these
two reaction systems are superior to the previously reported one for
several identical substrates in terms of ee and yield.
2) Percarbonate (1.5 eq.), Cat (0.2 eq),
Toluene/H2O, 0 o
C
Entry
Catalyst recovery (%)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
> 99
>99
>99
>99
99
98
97
98
97
70
74
73
73
74
72
73
71
69
64
97
96
97
95
96
96
96
96
95
93
10
96
a
Reaction conditions: aldehyde (2.0 mmol), Ketone (2.0 mmol), KOH (12 mmol),
H2O (6 mL), rt; then percarbonate (3.0 mmol), [3-apmim]Cl-PLL (0.4 mmol), toluene
(6 mL), 0 ꢀC.
Although aromatic aldehydes and ketones undergo this one-pot
CSC-asymmetric epoxidation chemistry can generally achieve high
enantioselectivities when they are performed in H2O/toluene het-
erogeneous solvent reaction system, the yields were only in the
range of moderate to good (55e76%, Table 2, entries 1e13). There-
fore, we decided to explore the possibility of increasing the yields
and maintaining the high enantioselectivities at the same time.
Thus, we developed a homogeneous solvent reaction system for this
purpose. The syntheses started with a ClaiseneSchmidt condensa-
tion of benzaldehyde and acetophenone with KOH in EtOH/H2O
solvent mixture, which was followed by an asymmetric epoxidation
in the presence of sodium percarbonate (1.5 equiv) and catalytic
amount of [3-apmim]Cl-PLL (0.2 equiv). This one-pot reaction se-
quence afforded the chiral epoxychalcone in 71% yield and 35%ee
(Table 4, entry 1). A number of different solvent mixtures have been
investigated in order to increase both of the yield and enantiose-
lectivity of the asymmetric epoxidation. The THF/H2O solvent sys-
tem turned out to be the best solvent system for this reaction (Table
4, entry 5 vs entries 1e4). Efforts to further improve the yield and
enantioselectivity by adjusting the ratio of THF/H2O homogeneous
Table 5
Synthesis of chiral epoxides with [3-apmim]Cl-PLL as catalyst in homogeneous
solvent reaction systema
O
O
1) 0.5 eq KOH, H2O/THF(3:1), RT
O
O
+
2) 1.5 eq Percarbonate, 0.2 eq Cat, 0oC
R2
R1
R2
R1
Entry
R1
Ph
R2
Yield (%)
ee (%)
1
2
Ph
Ph
Ph
Ph
Ph
Ph
84
69
89
83
76
81
87
76
80
81
75
75
83
95
74
94
93
88
80
82
72
94
97
95
95
97
o-MeOC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
m-FC6H4
Ph
Ph
Ph
Ph
Ph
3
4b
5
Table 4
Optimization of reaction conditions in homogeneous solvent reaction systema
6
7
8
9
10
11
12
13
O
O
O
O
o-BrC6H4
m-BrC6H4
p-BrC6H4
p-ClC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
1) KOH, Solvent, RT, 72h
+
2) 1.5 eq Percarbonate,
0.2eq Cat, RT,1h
Ph
Ph
Entry
Solvent (v:v)
Base (equiv)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
EtOH/H2O (1:1)
MeOH/H2O (1:1)
DME/H2O (1:1)
MeCN/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (1:1)
THF/H2O (3:1)
THF/H2O (1:3)
THF/H2O (1:3)
1.0
1.0
1.0
1.0
1.0
0.5
1.5
5.0
0.5
0.5
0.5
71
78
69
64
78
80
78
79
72
84
84
35
51
92
82
92
92
88
85
87
92
95
a
Reaction conditions: aldehyde (3.0 mmol), ketone (3.0 mmol), KOH (1.5 mmol),
solvent mixture (45 mL), rt, 72 h; then percarbonate (4.5 mmol), [3-apmim]Cl-PLL
(0.6 mmol), 0 ꢀC, 1 h.
b
H2O/THF (1:1).
3. Conclusions
9
In this work, we have disclosed a convenient and efficientone-pot
10
process for production of chiral
a,b-epoxy ketones directly
11b
from benzaldehydes and acetophenones catalyzed by a chiral mod-
ified poly(amino acid). Two effective reaction systems with com-
plementary high enantioselectivities or satisfactory yields have been
developed for this purpose. Importantly, the chiral poly(amino acid)
a
Reaction conditions: benzaldehyde (3.0 mmol), acetophenone (3.0 mmol), KOH
(1.5e15 mmol), mixed solvent (45 mL), rt, 72 h; then percarbonate (4.5 mmol), [3-
apmim]Cl-PLL (0.6 mmol), rt, 1 h.
b
The epoxidation was performed at 0 ꢀC.

5292
W. Luo et al. / Tetrahedron 67 (2011) 5289e5292
catalyst is insoluble in either water or common organic solvents, and
it can be simply filtered and reused in the next batch of reaction. The
recycled catalyst has been continuously reused and recycled for 10
times without losing its catalytic efficiency in terms of both enan-
tioselectivity and yield.
4.4. General procedure for PLL catalyst recycle and reuse
Aldehyde (2.0 mmol), ketone (2.0 mmol), and 50% KOH aqueous
solution (1.4 g, 12.0 mmol) was stirred at 25 ꢀC until the reaction
was complete (detected by TLC). Then, toluene (6.0 mL), water
(6.0 mL), percarbonate (3.0 mmol) and the recovered catalyst
(20 mol %) were added, the reaction mixture was stirred at 0 ꢀC
until the enone disappeared (detected by TLC). The catalyst was
recovered by rapid filtration and washed with ethyl acetate. The
product work-up procedure was the same as the above-mentioned
method.
4. Experimental
4.1. General methods
1H NMR spectra were measured on a Bruker 400 MHz spec-
trometer at 25 ꢀC in CDCl3 with TMS as the internal standard.
Chemical shifts are given in parts per million (d-scale), and coupling
Acknowledgements
constants and widths of multiplets are given in hertz. 13C NMR
spectra were measured on a spectrameter (13C at 100 MHz). The
imidazolium-modified PLL ([3-apmim]Cl-PLL) catalyst was syn-
thesized according to the reported method.21 HRMS were recorded
on a Bruker micrOTOF II spectrometer (ESI ionization). The ee was
determined by chiral-phase HPLC analysis on a Chiralpak AD col-
umn (eluent 10% i-PrOH in hexane, UV detection at 254 nm).
This research was financially supported by the National Natural
Science Foundation of China (Grant No. 20772032) and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes. We
also thank the Laboratory of Organic Functional Molecules, Sino-
French Institute of ECNU for support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.024.
4.2. General procedure for the one-pot
condensationeepoxidation in homogeneous solvent reaction
system
References and notes
Aldehyde (3 mmol), ketone (3 mmol) was dissolved in THF
(22.5 mL) and water (22.5 mL), KOH(1.5 mmol) was added and the
mixture was stirred at 25 ꢀC for 72 h. Then percarbonate (1.5 mmol)
and catalyst (20 mol %) were added, the reaction mixture was
stirred at 0 ꢀC until the enone disappeared (detected by TLC). The
catalyst was recovered by rapid filtration and washed with ethyl
acetate. The combined organic fractions were dried over anhydrous
Na2SO4, and were then evaporated in vacuo and purified by silica
gel column chromatography (AcOEt/petroleum 1:10e1:30) to af-
ford the corresponding epoxide.
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Aldehyde (1.0 mmol), ketone (1.0 mmol), and 50% KOH aqueous
solution (0.7 g, 6.0 mmol) was stirred at 25 ꢀC until the reaction was
complete (detected by TLC). Then toluene (3.0 mL), water (3 mL),
percarbonate (1.5 mmol), and catalyst (20 mol %) were added, the
reaction mixture was stirred at 0 ꢀC until the enone disappeared
(detected by TLC). The catalyst was recovered by rapid filtration and
washed with ethyl acetate. The product work-up procedure was the
same as the above-mentioned method.