Enantioselective epoxidation of α,β-unsaturated ketones using polymer-supported lanthanoid-BINOL complexes

Article abstract of DOI:10.1016/S0957-4166(03)00282-9

The immobilization of chiral lanthanum and/or ytterbium complexes using polymer-support is described. The heterogeneous catalysts obtained promote the enantioselective epoxidation of α,β-unsaturated ketones affording the products in good yields with high enantiomeric excess. The catalysts were easily separated from the products by washing with ether and the recovered catalysts promote the enantioselective epoxidation reaction effectively maintaining the high level of enantioselectivity obtained during the first run.

Full text of DOI:10.1016/S0957-4166(03)00282-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1587–1592
Enantioselective epoxidation of a,b-unsaturated ketones using
polymer-supported lanthanoid–BINOL complexes
Doss Jayaprakash, Yukari Kobayashi, Shizue Watanabe, Takayoshi Arai and Hiroaki Sasai*
The Institute of Scientific and Industrial Research, Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
Received 10 March 2003; accepted 26 March 2003
Abstract—The immobilization of chiral lanthanum and/or ytterbium complexes using polymer-support is described. The
heterogeneous catalysts obtained promote the enantioselective epoxidation of a,b-unsaturated ketones affording the products in
good yields with high enantiomeric excess. The catalysts were easily separated from the products by washing with ether and the
recovered catalysts promote the enantioselective epoxidation reaction effectively maintaining the high level of enantioselectivity
obtained during the first run. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Herein we report the immobilization of enantioselective
epoxidation catalysts using polymeric ligands contain-
ing BINOL. Using lanthanum and ytterbium complexes
generated with sterically regular polymeric BINOL
derivatives we have recently reported the epoxidation of
chalcone 2 and benzalacetone 4.9 Contrary to our
expectations the epoxidation catalysts afforded the
products with lower enantioselectivities. Moreover
yields and selectivities were found to decrease when
attempts were made to reuse the catalysts. In search of
better alternatives for this catalytic system we explored
the use of polymer supported BINOL 17 as a chiral
ligand. Chalcone and benzalacetone were used as test
substrates in this study.
Catalytic enantioselective epoxidation of a,b-unsatu-
rated ketones offers a convenient procedure for the
synthesis of epoxy ketones. A variety of catalytic sys-
tems employing polyamino acid catalysts,1 asymmetric
phase-transfer catalysts,2 and chiral ligand–metal
catalysts3 have been developed. Recently the use of
lanthanoid–BINOL complexes as catalysts for the cata-
lytic enantioselective epoxidation of enones by
hydroperoxides have been studied in great detail.4 This
catalytic system is applicable for both alkyl and aryl
substituted enones giving the products in high yields
with good enantioselectivity.
With the growing importance of polymer supported
reagents and catalysts that offer methods to recover
and reuse expensive chiral catalysts, considerable atten-
tion has been focused on the use of macromolecules,
both soluble5 and insoluble,6 containing chiral 1,1%-bi-2-
naphthol (BINOL) for the immobilization of a range of
asymmetric catalysts. We have also reported the use of
polymer5h,7 and dendrimer8 supported BINOL as the
chiral ligand for the immobilization of AlLibis(binaph-
thoxide) catalyst. These immobilized catalysts pro-
moted the asymmetric Michael addition of dibenzyl
malonate to 2-cyclohexenone affording the product in
high enantiomeric excess. The heterogeneous nature of
these catalysts facilitated their recovery and reuse.
2. Results and discussion
Addition of La(O-i-Pr)3 to a THF solution containing 1
resulted in a pale yellow precipitate. This precipitate
La-1 catalyzed the enantioselective epoxidation of 2
* Corresponding author. Tel.: +81-6-6879-8465; fax: +81-6-6879-8469;
e-mail: sasai@sanken.osaka-u.ac.jp
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00282-9

1588
D. Jayaprakash et al. / Tetrahedron: Asymmetry 14 (2003) 1587–1592
with cumene hydroperoxide (CMHP) in the presence of
MS 4A. The product epoxide 3 was obtained in 30%
yield with 65% e.e. after 22 h (Table 1, entry 1). The
activity of the catalyst was greatly enhanced by the
addition of 15 mol% of Ph3PꢀO and the product was
obtained in 96% yield with 98% e.e. in 20 h (entry
2).4d,4f Although the catalyst requires longer reaction
times, the chemical yield and the enantioselectivity
offered are close to those obtained with the soluble
parent catalysts.4 The use of tert-butyl hydroperoxide
(TBHP) as the oxidant afforded the product in 97%
yield with 83% e.e. after 20 h (entry 3). Under similar
conditions 4 was converted to the epoxide 5 in 86%
yield with 82% e.e. after 18 h (entry 4). Addition of dry
ether to the reaction mixture facilitated the separation
of the catalyst and the reaction mixture. The clear
supernatant solution was syringed out and the catalyst
washed three times with ether followed by THF twice.
The catalyst thus obtained as a dark brown solid was
found to promote the epoxidation of 2, however the
product was obtained in 61% yield with 62% e.e. after
20 h (entry 5). While the exact reason for the decrease
in activity is not clear at present, it could be in part due
to the removal of the additive during washing by ether
as the enantioselectivity obtained in the second run is
comparable to that obtained in the absence of the
additive (entry 1). In fact upon the addition of Ph3PꢀO
during the second run the product was obtained in 88%
yield with 85% e.e. although the reaction time was
longer (entry 6). Addition of MS 4A during the second
run did not have any impact on the yield and selectivity
(entry 7). The observed results are consistent with a
recent report by Inanaga et al. wherein the activity of
the lanthanum complex of BINOL dropped drastically
with aging.4f
In an attempt to generate more stable complexes that
would afford higher enantioselectivity for the epoxida-
tion of 4 with TBHP, attention was focused on the
ytterbium complex Yb-1 obtained as a pale yellow solid
by the reaction of 1 with Yb(O-i-Pr)3 in a metal to
ligand ratio of 2:3.4b Since water is known to be a good
additive for this type of catalyst the epoxidation of 4
was performed in the presence of 4 equiv. of water with
respect to ytterbium.4b The product was obtained in
62% yield with 86% e.e. after 23 h (Table 2, entry 1). In
our previous report with polymeric BINOL ligands
Ph3PꢀO was found to be more effective than water.9
However, in the present study use of Ph3PꢀO (15 mol%)
did not result in improvement and the product was
obtained in 59% yield with 87% e.e. in 24 h (entry 2).
Moreover, a decrease in the chemical yield and enan-
Table 1. Enantioselective epoxidation of enones catalyzed by polymer-supported La–BINOL complex
Entry
Substrate
Ph3PꢀO (mol%)
R%OOH
Time (h)
Yield (%)a
E.e. (%)b
1
2
3
4
2
2
2
4
2
2
2
–
CMHP
CMHP
TBHP
TBHP
CMHP
CMHP
CMHP
22
20
20
18
20
67
67
30
96
97
86
61
88
91
65
98
83
82
62
85
84
15
15
15
–
15
15
5c
6c
7d
a Isolated yields after column chromatography.
b Determined by HPLC analysis (Daicel Chiralcel OD column).
c Catalyst from entry 2 was reused.
d Catalyst from entry 2 was reused with MS 4A.
Table 2. Enantioselective epoxidation of 4 catalyzed by polymer-supported Yb–BINOL complex Yb-1
Entry
Additive
Ph3PꢀO (mol%)
Time (h)
Yield of 5 (%)b
E.e. of 5 (%)c
H2O (equiv.)a
1
4
–
–
4
4
–
23
24
38
20
22
62
59
49
58
44
86
87
82
91
91
2
15
15
15
15
3d
4
5d
a Equivalents with respect to Yb(O-i-Pr)3.
b Isolated yields after column chromatography.
c Determined by HPLC analysis (Daicel Chiralpak AD-H column).
d Catalyst reused after washing with ether and THF.

D. Jayaprakash et al. / Tetrahedron: Asymmetry 14 (2003) 1587–1592
1589
the monomer 7. Polymer 8 [Mw=8548 (PDI=1.5)] was
then obtained by free radical co-polymerization of 7
with 4 equiv. of styrene. The protecting groups were
finally removed by acid treatment to get polymer 9.
Polymer 9 afforded the catalyst as a pale yellow solid
upon treatment with Yb(O-i-Pr)3 in THF in the pres-
ence of MS 4A. This catalyst was also found to be
effective in promoting the enantioselective epoxidation
of 4 with TBHP. The results are presented in Table 3.
The product epoxide was obtained in 52% yield with
84% e.e. after 22 h with the use of water as additive
(Table 3, entry 1). In the presence of both water and
Ph3PꢀO as additives the catalyst afforded the product
in 48% yield with 84% e.e. (entry 2). Since the oxygen
atom of the ether linkage present in the polymer could
also coordinate to the metal center the presence of both
additives might make the complex crowded thereby
reducing its activity. Thus with only Ph3PꢀO as additive
the reaction afforded the product in 69% yield with
88% e.e. after 22 h (entry 3). When the catalyst was
reused after washing with ether and THF the product
was obtained in 48% yield with 85% e.e. (entry 4).
Unlike the case of the Yb-1 complex the reaction rate
with Yb-9 was found to be dependent on the amount of
Ph3PꢀO used. When only half the amount of Ph3PꢀO
(7.5 mol%) was used the reaction was much faster
affording the product in 90% yield in 18 h with the
enantioselectivity remaining unchanged (entry 5).
Moreover, this catalyst maintained the enantioselectiv-
ity even upon being reused twice although the chemical
yield was decreased on first reuse (entries 6 and 7). The
fact that higher reactivity could be achieved even in the
absence of water and with lower amounts of Ph3PꢀO
suggests the positive influence of the bulky polymer on
the catalytic activity.
Scheme 1. Reagents and conditions: (i) NaH, THF–DMF,
0°C, 30 min; then 4-vinyl-benzylchloride, rt, 24 h; (ii) styrene
(4 equiv.), AIBN, toluene, 75°C, 56 h; (iii) HCl, THF, 0°C“
rt, 15 h.
tioselectivity was observed when the heterogeneous cat-
alyst was reused (entry 3). Combined use of water and
Ph3PꢀO afforded the product in 58% yield with 91%
e.e. in 20 h (entry 4). Interestingly in the present system
the reused catalyst maintained the high level of enan-
tioselectivity obtained during the first cycle although a
decrease in chemical yield was observed (entry 5). While
Ph3PꢀO is required for higher reaction rates the pres-
ence of water is important for obtaining higher enan-
tioselectivity and maintaining it in the case of reused
catalyst.
In order to study the effect of the bulky polymer on the
catalytic center another polymeric BINOL was pre-
pared using the known 3-hydroxymethyl BINOL
derivative 64a as shown in Scheme 1. Alcohol 6 was
coupled to 4-vinylbenzylchloride by etherification to get
Thus under all conditions the chiral La and Yb com-
plexes generated with 1 or 9 as ligand were found to
afford epoxides with high enantioselectivities. In addi-
tion these catalysts maintained high levels of enantiose-
lectivities when attempts were made to reuse them.
Table 3. Enantioselective epoxidation of 4 catalyzed by polymer-supported Yb–BINOL complex Yb-9a
Entry
Additive
Ph3PꢀO (mol%)
Time (h)
Yield of 5 (%)c
E.e. of 5 (%)d
H2O (equiv.)b
1
2
4
4
–
–
–
–
–
–
22
24
22
22
18
18
36
52
48
69
48
90
62
60
84
84
88
85
88
89
88
15
15
15
3
4e
5
7.5
6e
7f
7.5
7.5
a Metal to ligand ratio was 2:3.
b Equivalents with respect to Yb(O-i-Pr)3.
c Isolated yields after column chromatography.
d Determined by HPLC analysis (Daicel Chiralpak AD-H column).
e Catalyst was reused after washing with ether and THF.
f Third use of the catalyst.

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D. Jayaprakash et al. / Tetrahedron: Asymmetry 14 (2003) 1587–1592
3. Conclusion
1H), 7.41–7.15 (m, 11H), 7.55 (d, J=9.1 Hz, 1H), 7.84
(t, J=9.1 Hz, 1H), 7.93 (d, J=9.1 Hz, 1H), 8.09 (s,
1H); 13C NMR (CDCl3) l 55.9, 56.5, 68.1, 72.5, 94.8,
99.2, 113.7, 116.4, 120.6, 124.0, 124.8, 125.2, 125.4,
125.5, 125.9, 126.1, 126.5, 127.7, 127.8, 127.9, 128.2,
129.5, 129.7, 130.7, 131.6, 133.8, 136.4, 136.9, 137.7,
151.6, 152.6; FAB MS m/z 543 [M+Na]+.
To conclude, heterogeneous epoxidation catalysts were
generated by the reaction of polymer supported
BINOLs 1 or 9 with La(O-i-Pr)3 or Yb(O-i-Pr)3. These
catalysts effectively promoted the enantioselective epox-
idation of 2 and 4 affording the product epoxides in
good yields with high enantioselectivity. In addition the
catalysts could be reused after washing with ether and
THF and were found to maintain high levels of enan-
tioselectivity. The results obtained with this ligand sys-
tem are much better compared to that obtained earlier
with sterically regular polymeric BINOL.9 Attempts to
enhance the activity of these catalysts to obtain higher
chemical yield and enantioselectivity are underway.
4.3. Synthesis of the polymer-supported BINOL 8
To a toluene solution of 7 (0.6 g, 1.15 mmol in 2 mL)
was added AIBN (0.053 g) and styrene (0.53 mL, 4.8
mmol). The solution was purged with argon thoroughly
and polymerization was carried out at 75°C for 56 h.
After cooling to rt the polymer was precipitated by
addition to methanol. The precipitate was filtered, dis-
solved in CH2Cl2 and reprecipitated by addition to
n-hexane. The white solid thus obtained was dried in
vacuo at 50°C for 3 h to give the polymer 8 (0.857 g,
79% yield). [h]2D3 +30.3 (c 0.50, CHCl3); Mw=8548
[Mn=5594, PDI=1.5]; IR (neat) 2918, 1593, 1240,
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded with JEOL
JNM-EX270 FT NMR system. IR spectra were
recorded on Shimadzu FTIR 8300. Optical rotations
were measured with a JASCO P-1030 polarimeter.
HPLC analyses were performed on a JASCO HPLC
system (JASCO PU 980 pump and UV-975 UV–vis
detector) using a mixture of n-hexane and i-PrOH as
the eluent. Molecular weights of the polymers were
determined by gel permeation chromatography (GPC)
relative to polystyrene standards using SHODEX GPC
KF 803L column. 2 and 4 were obtained from commer-
cial sources. Chalcone was recrystallized from EtOH.
Toluene solutions of anhydrous TBHP and anhydrous
CMHP were prepared using literature procedures.4a All
reactions were performed under an argon atmosphere.
THF was freshly distilled from sodium benzophenone
ketyl. MS 4A was dried in vacuum at 180°C for 3 h
before use. Polymer 1 was prepared by the synthetic
route reported by us earlier.7
1151, 1012 cm−1; H NMR (CDCl3) l 0.88 (br), 1.08
1
(br), 1.40 (br), 1.80 (br), 2.80 (br) 3.11 (br), 4.56 (br),
4.87 (br), 4.98 (br), 5.07 (br), 6.55 (br), 7.06 (br) 7.18
(br), 7.30 (br), 7.55 (br), 7.86 (br), 7.92 (br), 8.07 (br).
4.4. Removal of the protecting groups in 8
To an ice cooled solution of the polymer 8 (800 mg) in
THF (2 mL) was added a THF solution of HCl (1 mL
conc. HCl in 4 mL of THF). The solution was allowed
to warm to rt. After being stirred for 15 h the solution
was poured into water (50 mL). The product was
extracted with CH2Cl2 and precipitated by addition to
n-hexane twice. The precipitated polymer 9 was dried in
vacuo at 50°C for 3 h (600 mg). [h]2D3 +15.0 (c 0.51,
CHCl3); IR (neat) 3030, 2918, 1596, 1099 cm−1; 1H
NMR (CDCl3) l 0.88 (br), 1.08 (br), 1.42 (br), 1.77
(br), 4.54 (br), 4.82 (br), 5.03 (br), 6.54 (br), 7.03 (br),
7.26 (br), 7.84 (br).
4.2. Synthesis of (R)-3-(4-vinylbenzyloxy)methyl-2,2%-
bis(methoxymethyloxy)-1,1%-binaphthalene 7
4.5. Procedure for the enantioselective epoxidation of 2
catalyzed by polymer-supported La–BINOL complex
La-1
To an ice cooled solution of 6 (0.92 g, 2.27 mmol) in
THF and DMF (15 mL+10 mL) was added NaH (133
mg, 3.35 mmol as 60% purity in oil) and the mixture
stirred for 30 min. To this suspension was then added
4-vinyl benzylchloride (0.32 mL, 2.27 mmol). The mix-
ture was allowed to warm to rt and stirred for 24 h.
The reaction was quenched by addition of saturated
NaCl solution. The product was extracted with ethyl
acetate (20 mL×3) and dried over anhydrous Na2SO4.
The crude product obtained upon evaporation of the
solvent was subjected to flash chromatography (silica
gel, n-hexane/ethyl acetate, 9/1) to get 1.06 g of the
product 7 in 89% yield as a colorless pasty mass. [h]D28
+50.2 (c 1.12, CHCl3); IR (neat) 2896, 1591, 1238, 1147,
MS 4A (100 mg), Ph3PꢀO (21 mg, 15 mol%) and 1 (25
mg, 0.025 mmol as a monomer) were added to a dry
reaction vessel and purged with argon. THF (0.5 mL)
was then added at rt followed by La(O-i-Pr)3 (0.25 mL,
0.1 M in THF, 0.025 mmol) in drops. The resulting
pale yellow suspension was stirred for 1 h and anhy-
drous cumene hydroperoxide (0.3 mL, 1.5 equiv., 0.75
mmol, 2.6 M solution in toluene) was added. After
being stirred for 10 min 2 (104 mg, 0.5 mmol) was
added and the reaction was allowed to proceed at rt for
20 h during which the reaction mixture developed a
dark brown color. Dry ether was then added and the
brown solid was allowed to settle down. The superna-
tant solution was removed with a syringe and the
catalyst washed with ether three times. The ether
extract was quenched with saturated. aq. NH4Cl, sepa-
rated and dried over anhydrous Na2SO4. Removal of
the solvent under reduced pressure gave an oily residue,
1
1008 cm−1; H NMR (CDCl3) l 2.82 (s, 3H), 3.14 (s,
3H), 4.53 (d, J=5.4 Hz, 1H), 4.61 (d, J=5.4 Hz, 1H),
4.73 (s, 2H), 4.90 (s, 2H), 4.99 (d, J=6.9 Hz, 1H), 5.09
(d, J=6.9 Hz, 1H), 5.22 (dd, J=10.9, 0.9 Hz, 1H), 5.72
(dd, J=17.6, 0.9 Hz, 1H), 6.67 (dd, J=17.6, 10.9 Hz,

D. Jayaprakash et al. / Tetrahedron: Asymmetry 14 (2003) 1587–1592
1591
which was purified by flash chromatography (silica gel,
n-hexane/ethyl acetate=30/1) to give 108 mg of the
epoxide 3 in 96% yield with 98% e.e. Enantiomeric
excess was determined by chiral stationary phase HPLC
(Daicel Chiralcel OD column, 1/49 i-PrOH/n-hexane, 1
mL/min, 254 nm, 16.0 min (major isomer) and 17.8 min
(minor isomer)).
mmol) was added and the reaction was allowed to
proceed at rt. After 18 h dry ether was added and the
brown solid was allowed to settle down. The superna-
tant solution was removed with a syringe and the
catalyst washed with ether three times. The ether
extract was quenched with saturated. aq. NH4Cl, sepa-
rated and dried over anhydrous Na2SO4. Removal of
the solvent under reduced pressure gave an oily residue
that was purified by flash chromatography (silica gel,
n-hexane/CH2Cl2=1/10) to give 73 mg of 5 in 90%
yield with 88% e.e. Enantiomeric excess was determined
by chiral stationary phase HPLC analysis.
4.6. Procedure for the enantioselective epoxidation of 4
catalyzed by polymer-supported Yb–BINOL complex
Yb-1
4.6.1. First cycle. MS 4A (50 mg) and 1 (18.8 mg, 0.018
mmol as a monomer) were added to a dry reaction
vessel and purged with argon. THF (0.5 mL) was then
added at rt followed by Yb(O-i-Pr)3 (0.25 mL, 0.05 M
in THF, 0.0125 mmol) in drops. The resulting pale
yellow suspension was stirred for 1 h and H2O (0.1 mL,
0.5 M in THF) was added followed by Ph3PꢀO (10 mg,
15 mol%) and anhydrous TBHP (0.09 mL, 1.5 equiv.,
0.375 mmol, 4.8 M solution in toluene). After being
stirred for 10 min 4 (37.5 mg, 0.25 mmol) was added
and the reaction was allowed to proceed at rt. After 20
h dry ether was added and the brown solid was allowed
to settle down. The supernatant solution was removed
with a syringe and the catalyst washed with ether three
times. The ether extract was quenched with saturated.
aq. NH4Cl, separated and dried over anhydrous
Na2SO4. Removal of the solvent under reduced pres-
sure gave an oily residue that was purified by flash
chromatography (silica gel, n-hexane/CH2Cl2=1/10) to
give 23 mg the epoxide 5 in 58% yield with 91% e.e.
Enantiomeric excess was determined by chiral station-
ary phase HPLC analysis (Daicel Chiralpak AD-H
column, 1/49 i-PrOH/n-hexane, 0.6 mL/min, 254 nm,
21.3 min (minor isomer) and 24.6 min (major isomer)).
4.7.2. Reuse of the catalyst. The brown solid obtained at
the end of the reaction was suspended in dry THF
followed by the addition of Ph3PꢀO (10 mg, 7.5 mol%).
After being stirred for 10 min anhydrous TBHP (0.18
mL, 1.5 equiv., 0.75 mmol, 4.8 M solution in toluene)
and 4 (73 mg, 0.5 mmol) were added and reaction was
allowed to proceed at rt for 18 h. Dry ether was added
to separate the product and the catalyst repeatedly
washed with ether. The ether extract after quenching
and purification by flash chromatography afforded 50
mg of 5 in 62% yield and 89% e.e.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan. We thank the technical
staff in the Materials Analysis Center of ISIR, Osaka
University.
References
4.6.2. Reuse of the catalyst. The brown solid obtained at
the end of the reaction was suspended in dry THF
followed by the addition of H2O (0.1 mL, 0.5 M in
THF) and Ph3PꢀO (10 mg, 15 mol%). After being
stirred for 10 min anhydrous TBHP (0.09 mL, 1.5
equiv., 0.37 mmol, 4.8 M solution in toluene) and 4
(37.5 mg, 0.25 mmol) were added and reaction was
allowed to proceed at rt for 22 h. Dry ether was added
to separate the product and the catalyst repeatedly
washed with ether. The ether extract after quenching
and purification by flash chromatography afforded 18
mg of 5 in 44% yield and 91% e.e.
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4.7. Procedure for the enantioselective epoxidation of 4
catalyzed by polymer-supported Yb–BINOL complex
Yb-9
4.7.1. First cycle. MS 4A (100 mg) and 9 (37.5 mg,
0.037 mmol as a monomer) were weighed into a dry
reaction vessel and purged with argon. THF (0.5 mL)
was then added at rt followed by Yb(O-i-Pr)3 (0.5 mL,
0.05 M in THF, 0.025 mmol) in drops. The resulting
pale yellow suspension was stirred for 1 h and PPh3ꢀO
(10 mg, 7.5 mol%) was added followed by anhydrous
TBHP (0.18 mL, 1.5 equiv., 0.75 mmol, 4.8 M solution
in toluene). After being stirred for 10 min 4 (73 mg, 0.5
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