Self-supported BINOL-Zn catalysts for heterogeneous enantioselective epoxidation of (E)-α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2009.02.151

A class of chiral self-supported catalysts prepared from bis-BINOL ligands and diethyl zinc were successfully applied in the hetereogeneous enantioselective epoxidation of a range of (E)-α,β-unsaturated ketones, affording the corresponding epoxy ketones in high enantioselectivity. The self-supported catalysts were easily recovered from the reaction mixture and were reusable for several consecutive runs.

Full text of DOI:10.1016/j.tetlet.2009.02.151

Tetrahedron Letters 50 (2009) 2200–2203
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Self-supported BINOL–Zn catalysts for heterogeneous enantioselective
epoxidation of (E)-
a,b-unsaturated ketones
*
Haiming Wang, Zheng Wang, Kuiling Ding
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A class of chiral self-supported catalysts prepared from bis-BINOL ligands and diethyl zinc were success-
Received 6 December 2008
Revised 18 February 2009
Accepted 20 February 2009
Available online 25 February 2009
fully applied in the hetereogeneous enantioselective epoxidation of a range of (E)-a,b-unsaturated
ketones, affording the corresponding epoxy ketones in high enantioselectivity. The self-supported cata-
lysts were easily recovered from the reaction mixture and were reusable for several consecutive runs.
Ó 2009 Elsevier Ltd. All rights reserved.
The asymmetric epoxidation of
a
,b-enones is a useful approach
As a preliminary test of the plausibility, the self-supported cat-
alyst L1–Zn, readily prepared by reaction of the bis-BINOL ligand
L18e (Chart 1) with diethyl zinc, was examined for the epoxidation
using chalcone 1a as a model substrate with CMHP as the oxidant.
The addition of two molar equivalents of diethylzinc in hexane to a
stirred solution of the bis-BINOL ligand L1 in Et2O resulted in
immediate precipitation of a white amorphous solid of L1–Zn,
which, after 10 min of stirring the mixture at room temperature,
was isolated by filtration under argon. The resultant solid was vir-
tually insoluble in all organic solvents (CH2Cl2, CHCl3, THF, DMSO,
toluene, diethyl ether, t-butyl methyl ether, 1,4-dioxane, ethyl
to optically active epoxy ketones, which are versatile intermediates
for the synthesis of many natural products or biologically active
compounds.1 Over several decades of development, a number of
valuable catalytic methodologies have been established for effi-
cient asymmetric induction,2 mainly involving the use of chiral
metal peroxides,3 asymmetric phase transfer catalysts,4 polyamino
acid catalysts,5 chiral dioxiranes,6 or other organocatalysts.7 While
excellent enantioselectivities have been achieved in many cases,
the productivities of the catalysts were often not ideal, which
necessitated fairly high loadings of the expensive chiral catalysts.
Therefore, further development of recoverable chiral catalysts for
the efficient asymmetric epoxidation of various enones is a highly
desirable goal toward practical applications. To this end, our group
have developed a series of reusable chiral BINOL–La-Ph3PO3e,f cat-
alysts based on the self-supporting strategy,8 and demonstrated
their excellent performance in the heterogeneous catalysis of the
X
Y
Y
OH
OH
asymmetric epoxidation of a
,b-unsaturated ketones.8i As an effort
linker
HO
HO
to develop cheaper and even more versatile self-supported cata-
lysts for the titled reaction, we decided to investigate the catalytic
potential of analogous systems based on other chiral metal com-
plexes. The chiral BINOL–Zn catalyst reported by Minatti and
Dötz appears attractive in this aspect.3c,d Compared to the BI-
NOL–La-Ph3PO3e,f system, BINOL–Zn prepared from BINOL9 and
diethylzinc is a much less expensive catalyst, yet proved quite
effective for the epoxidation of enones bearing either aryl- and/or
alkyl-substituents, resulting in the corresponding products in good
yields and ee values. In this Letter, we wish to report the prelimin-
ary results in the heterogeneous asymmetric catalysis of epoxida-
tion of enones, using the in situ prepared chiral self-supported
BINOL–Zn catalysts by taking the aggregating properties of BI-
NOL–Zn complexes,10 with cumene hydroperoxide (CMHP) as the
terminal oxidant.
Y
Y
X
linker
linker
L1 =
L2 =
X = H,
Y =Ph
X = Y = H
X = Y = H
L5 =
L6 =
X = Y
= H
L3 =
L4 =
X = Br, Y = H
X = H, Y = I
L7 =
X = Y
= H
* Corresponding author.
E-mail address: kding@mail.sioc.ac.cn (K. Ding).
Chart 1. Bridged bis-binol ligands.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.151

H. Wang et al. / Tetrahedron Letters 50 (2009) 2200–2203
2201
Table 1
Table 2
Preliminary survey of reusability of self-supported catalyst L1/Zn for epoxidation of
Screening of various bis-BINOL ligands in Zn-catalyzed heterogeneous epoxidation of
chalcone 1aa
chalcone 1aa
O
1) Ligand (10 mol %)
ZnEt2( 28 mol %), r.t.
O
O
1) L1 (10 mol %)
O
ZnEt2( 20 mol %), r.t., 15 min
O
O
2) oxidant (1.2 equiv.), r.t.
2) CMHP (1.2 equiv.), r.t.
1a
2a
1a
2a
Yieldb (%)
eec (%)
Run
Time (min)
Yieldb (%)
eec (%)
Entry
Ligand
Time (h)
1
2
3
4
5
6
30
45
45
45
60
90
99
99
78
42
54
54
78
82
85
85
88
85
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
5.5
5
4
16
19
5
76
99
82
11
93
60
88
91
84
89
38
10
89
88
5
a
Reactions were performed on 0.5-mmol scale of chalcone in Et2O (2 mL) at
a
room temperature.
The catalysts were prepared in 1,4-dioxane (3 mL) followed by removal of the
solvent in vacuo and the reactions were performed on 0.5-mmol scale of chalcone
in Et2O (2 mL) at room temperature.
b
The yield of isolated epoxide.
Determined by chiral HPLC.
c
b,c
See footnotes b and c in Table 1.
acetate, and 1,2-dichloroethane) tested, and thus fulfilling a basic
prerequisite for heterogeneous catalysis. Indeed, charging a cata-
lytic amount of the solid sequentially with chalcone and CMHP
in Et2O and stirring the mixture at rt for 30 min, afforded exclu-
sively the trans-epoxidation product in nearly quantitative yield
with an ee value of 78% (Table 1, entry 1). Upon completion of
the reaction, the solid catalyst was readily recovered from the reac-
tion mixture by filtration under argon. After recharging with the
reactants and the solvent (Et2O), the recovered catalyst was reused
for several runs (Table 1, entries 2–6). Intriguingly, the ee values of
the epoxidation product 2a underwent a slight increase during
successive recycling runs, whereas the reaction rate slowed down
gradually, presumably as a result of partial catalyst inactivation.
While the results were encouraging, a drawback was noted in that
after prolonged standing (24 h) in diethyl ether the catalyst lost
most of its activity for the epoxidation. Although the exact reason
was unknown, it is plausible that on prolonged standing in Et2O
solution, the catalyst assembly may have undergone an irreversible
change in structure, leading to the formation of a more stable but
inactive species. In such a case, shortening the reaction time period
seems to be crucial for the recycling of the catalyst.
Subsequently, we proceeded to optimize the conditions for the
above epoxidation based on the screening of the effects of various
reaction parameters, including the solvent dependence, catalyst
composition, and loading, the nature of the terminal oxidant (for
details, see Table S1 in Table S1 in Supplementary data). The reac-
tion proceeded smoothly in Et2O, but the enantioselectivity was
only moderate (78% ee). On the other hand, the coordinating sol-
vent 1,4-dioxane was found to considerably retard the reaction,
affording the epoxidation product in poor yield (27%) after long
reaction period (40 h). Nevertheless, the enantioselectivity was
excellent in this case, giving an optimal value of 95% ee for the
product among all the solvents tested. To reach an acceptable bal-
ance between the reactivity and enantioselectivity, we further
tested the catalyst preparation in 1,4-dioxane. After the solvent
was removed in vacuo, the solid residue L1/Zn was used in the
epoxidation of chalcone in diethyl ether with CMHP as the oxidant.
Gratifyingly, with this procedure the epoxidation product was ob-
tained in good yield (76%) and excellent ee (94%) within a reason-
able reaction period (7 h) (see Table S1 in Supplementary data).
Further screening of the epoxidation conditions indicated that an
L1/Et2Zn ratio of 1:2.8 at a 10 mol % loading of L1 (relative to chal-
cone) was the best catalyst composition, while CMHP turned out to
be optimal among the tested oxidants.
fects of a collection of bis-BINOL ligands L1–L7, featuring spacers
with distinct shapes and/or sizes or bearing different substituents
(X, Y) on the BINOL motifs (Chart 1). It was expected that such a
difference in the geometry and/or substituent pattern on the bridg-
ing ligand skeleton should exert some effects on the catalysis of
chalcone epoxidation, as a result of different microenvironment
around the active sites in the resulting bis-BINOL/Zn assemblies.8
Indeed, under the above optimized conditions, wherein all the
bis-BINOL/Zn catalysts were found insoluble in diethyl ether, wide
variations in either the reactivity or the enantioselectivity were ob-
served with different catalyst compositions, as summarized in Ta-
ble 2. While increasing the length of the spacer to some extent
seems to be beneficial for the catalytic reactivity (Table 2, entries
1, 2, and 6), introducing substituents other than H atoms at the
3,30-positions of the BINOL motifs is obviously unfavorable for
the catalysis, leading to a drastic degradation in product yield
and/or ee values (Table 2, entries 4 and 5). These facts imply that
the active species in the catalysis may be an aggregated multi nu-
clear Zn complex. Among all the catalysts tested, L1/Zn combina-
tion afforded the product with the highest ee value (91%), albeit
in a slightly inferior yield as compared with some cases (entries
2, 3, and 7). In order to further highlight the advantage of this
self-supported heterogeneous catalyst system, an analogous com-
plex generated from (R)-BINOL and ZnEt2 was examined in the
epoxidation of chalcone under the same experimental conditions.
Comparable yield (80%) and enantiomeric excess (95%) of the cor-
responding epoxide were obtained. Although the reaction mixture
in this case appeared to remain turbid throughout the process, a
significant amount of leached catalyst was observed in the filtrate.
In fact, the catalytic activity of filtration-recovered BINOL/ZnEt2
complex dramatically decreased on the consecutive reuses in the
epoxidation (see Supplementary data, Table S2).
With these results in hand, we turned to examine the asym-
metric epoxidation of various enones (1a–i) using L1/Zn as the
heterogeneous catalyst.11 As shown in Table 3, L1/Zn was quite
versatile for the enones bearing either a b-aryl or alkyl substitu-
ent on the double bond. For the b-aryl substituted enones bearing
electron-withdrawing groups, the corresponding epoxidation
products were obtained in good to excellent yields with high ee
values (Table 3, entries 2–6). Especially noteworthy is that the
protocol could successfully be extended to the epoxidation of b-
alkyl-substituted enones (Table 3, entries 7–9), which often con-
stitute a challenging type of substrates for most catalytic proto-
cols developed so far.
Having established the optimal reaction conditions of the pro-
cedure, we next shifted our attention to screen the structural ef-

2202
H. Wang et al. / Tetrahedron Letters 50 (2009) 2200–2203
Table 3
Acknowledgments
Enantioselective heterogeneous epoxidation of a
,b-unsaturated ketones with L1/Zna
Financial supports from the National Natural Science Founda-
O
O
1) L1 (10 mol %)
tion of China (No. 20632060, 20532050), the Chinese Academy of
Sciences, the Major Basic Research Development Program of China
(Grant No. 2006CB806106), the Science and Technology Commis-
sion of Shanghai Municipality and the Merck Research Laboratories
are gratefully acknowledged.
ZnEt2 (28 mol %), r.t.
R
R
O
2) CMHP (1.2 equiv.), r.t.
1a- 1i
2a- 2i
Entry
R
Time (h)
Epoxide
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Ph
5.5
4.5
4.5
4.5
4.5
5
6
6
15
2a
2b
2c
2d
2e
2f
2g
2h
2i
76
90
85
99
97
81
73
93
61
91
91
91
91
87
90
81
73
93
Supplementary data
4-ClC6H5
4-FC6H5
4-BrC6H5
4-NO2C6H5
2-BrC6H5
Et
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.151.
n-Pr
t-Bu
References
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See footnotes in Table 2.
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Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005, 105, 1603–1662; (b) Porter,
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In view of the persistent insolubility of the L1/Zn assembly in
the reaction systems, the heterogeneous nature of the catalysis
and the catalyst reuse were examined in the epoxidation of chal-
cone 1a (Table 4). The catalyst, prepared by mixing L1 with Et2Zn
in 1,4-dioxane followed by removal of the solvent, washing with
diethyl ether and drying in vacuo, was isolated as an amorphous
white solid. X-Ray powder diffraction analysis confirmed the
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cles. While the epoxidation proceeded smoothly in the presence of
the L1/Zn solid, the inactivity of the filtrate was consistent with the
heterogeneous nature of the catalysis. After completion of the reac-
tion, the solid catalyst L1/Zn was separated from the reaction mix-
ture by filtration under argon. The inductively coupled plasma
(ICP) spectroscopic analysis of the liquid phase showed that no
detectable zinc (<1 ppm) was leached into the solution. The recov-
ered solid catalyst was recharged with diethyl ether, chalcone, and
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enhancement in both reactivity and enantioselectivity during cat-
alyst recycle.
3. For selected references on the use of chiral-metal complexes in
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(b) Porter, M. J.; Roberts, S. M.; Skidmore, J. Bioorg. Med. Chem. 1999, 7, 2145–
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Chem. Soc 2008, 130, 6070–6071; (g) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L.
J. Am. Chem. Soc 2008, 130, 8134–8135.
8. For the concept of self-supporting strategy for chiral catalyst immobilization,
see reviews: (a) Ding, K.; Wang, Z. In Handbook of Asymmetric Heterogeneous
Catalysis; Ding, K., Uozumi, Y., Eds.; Sage: Weinheim, 2008; pp 323–355; (b)
Wang, Z.; Chen, G.; Ding, K. Chem. Rev. 2009, 109; (c) Ding, K.; Wang, Z.; Wang,
X.; Liang, Y.; Wang, X. Chem. Eur. J. 2006, 12, 5188–5197; (d) Ding, K.; Wang, Z.;
Shi, L. Pure Appl. Chem. 2007, 79, 1531–1540; For examples, see: (e) Guo, H.;
Wang, X.; Ding, K. Tetrahedron Lett. 2004, 45, 2009–2012; (f) Wang, X.; Ding, K.
J. Am. Chem. Soc. 2004, 126, 10524–10525; (g) Liang, Y.; Jing, Q.; Li, X.; Shi, L.;
Ding, K. J. Am. Chem. Soc. 2005, 127, 7694–7695; (h) Wang, X.; Wang, X.; Guo,
H.; Wang, Z.; Ding, K. Chem. Eur. J. 2005, 11, 4078–4088; (i) Wang, X.; Shi, L.; Li,
M.; Ding, K. Angew. Chem., Int. Ed. 2005, 44, 6362–6366; (j) Liang, Y.; Wang, Z.;
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9. For the preparation of BINOL, see: (a) Ding, K.; Wang, Y.; Zhang, L.; Wu, Y.;
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In summary, we have developed a class of chiral self-supported
bis-BINOL–Zn catalysts, which demonstrated good enantioselectiv-
ity and versatility in the heterogeneous catalysis of epoxidation of
enones. The procedure is operationally simple and the catalyst
could be easily recovered and reused several times. Further explo-
ration on the potential application of self-supporting strategy in
other catalytic reactions is underway in this laboratory.
Table 4
Recovery and reuse of the heterogeneous catalyst L1/Zn in the epoxidation of 1aa
Run
Time (h)
Yieldb (%)
Eec (%)
10. For examples: see: (a) Sakane, S.; Maruoka, K.; Yamamoto, H. Terahedron Lett.
1985, 26, 5535–5538; (b) Ding, K.; Ishii, A.; Mikami, K. Angew. Chem., Int. Ed.
1999, 38, 497–501; (c) Mikami, K.; Angelaud, R.; Ding, K.; Ishii, A.; Tanaka, A.;
Sawada, N.; Kudo, K.; Senda, M. Chem. Eur. J. 2001, 7, 730–737; (d)
Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1735–1738; (e) Du, H.; Long,
J.; Hu, J.; Lin, X.; Ding, K. Org. Lett. 2002, 4, 4349–4352; (f) Costa, A. M.; Jimeno,
C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929–
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Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466–2467; (h) Kumagai,
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Catal. 2005, 347, 1561–1568.
1a
2
3
5.5
5.5
9.5
9.5
24
3
3
3
3
20
76
80
54
38
42
99
99
89
63
81
91
92
86
69
54
90
93
91
84
72
4
5
1d
2
3
4
5
a,b,c
d
See footnotes in Table 2.
The loadings of L1 and Et2Zn were 15 mol % and 42 mol %, respectively, relative
11. Typical procedure for the asymmetric epoxidation: To
a Schlenk tube
to 1a.
containing stirred solution of ligand L1 (32.4 mg, 0.05 mmol) in 1,4-
a

H. Wang et al. / Tetrahedron Letters 50 (2009) 2200–2203
2203
dioxane (3 mL) was added dropwise a solution of ZnEt2 (0.14 mL, 0.14 mmol,
1.0 M solution in hexane) under argon. The resulted white turbid mixture
was stirred at rt for 15 min, followed by removal of the solvent under
reduced pressure. The residual white solid was charged with Et2O (2 mL) and
chalcone 1a (104 mg, 0.5 mmol), and the resultant mixture was stirred at rt
for 5 min before addition of CMHP (0.11 mL, 0.6 mmol, 80% solution in
cumene). The mixture was stirred at rt for a period of time indicated in Table
4. The reaction process was monitored by TLC. After the reaction, the solid
was isolated from the mixture by filtration under argon, washed twice with
Et2O, and recharged with Et2O (2 mL), chalcone 1a (104 mg, 0.5 mmol) and
CMHP (0.11 mL, 0.6 mmol, 80% solution in cumene) for the next run. The
combined filtrate was quenched with aq NaHSO3 (5 mL), extracted with
EtOAc (3 ꢀ 10 mL), and the combined organic phase was washed with aq
Na2CO3 and brine, and dried with MgSO4. The solvent was removed on a
rotary evaporator and the residue was purified by column chromatography
on silica gel with petroleum ether/ethyl acetate (20:1) as eluent to give the
epoxide 2a as a white solid (85 mg, 76% yield). 1H NMR (300 MHz, CDCl3): d
8.00 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.42–
7.36 (m, 5H), 4.31 (d, J = 1.8 Hz, 1H), 4.07 (d, J = 1.8 Hz, 1H). The enantiomeric
excess was determined by chiral HPLC analysis (DAICEL Chiralpak OB-H,
hexane/2-propanol = 60:40, flow rate = 0.5 mL/min, 20 °C, k = 254 nm;
retention time: 22.2 min (major), 27.8 min (minor); 91% ee); ½a D20
ꢁ
+199.1 (c
0.58 in CH2Cl2) [lit.3d
with 90% ee].
½ ꢁ +207.7 (c 0.78 in CH2Cl2) for 2S, 3R enantiomer
a 2D6