Asymmetric epoxidation of α,β-unsaturated ketones catalyzed by silica-grafted poly-(L)-leucine catalysts

Article abstract of DOI:10.1016/j.tetlet.2005.06.096

A practical procedure has been developed for grafting poly(amino acid) on silica gel as an efficient and recoverable catalyst in the Juliá-Colonna asymmetric epoxidation with high enantioselectivities. Separation and recovery of the catalyst of poly(amino

Full text of DOI:10.1016/j.tetlet.2005.06.096

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5665–5668
Asymmetric epoxidation of a,b-unsaturated ketones catalyzed
by silica-grafted poly-(L)-leucine catalysts
Hua Yi,a Gang Zou,a Qiang Li,a Qun Chen,b Jie Tanga,* and Ming-yuan Hea
aDepartment of Chemistry, East China Normal University, 3663 ZhongShan(N) Road, Shanghai 200062, China
bKey Laboratory of Optical and Magnetic Resonance Spectroscopy, East China Normal University,
3663 Zhongshan(N) Road, Shanghai 200062, China
Received 24 January 2005; revised 17 June 2005; accepted 20 June 2005
Abstract—A practical procedure has been developed for grafting poly(amino acid) on silica gel as an efficient and recoverable
´
catalyst in the Julia–Colonna asymmetric epoxidation with high enantioselectivities. Separation and recovery of the catalyst of
poly(amino acid) have been remarkably improved by grafting on silica gel without a significant loss of enantioselectivity and
activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Alkenes epoxidation is among the most widely useful
asymmetric transformations. This reflects both the effec-
tiveness of existing epoxidation protocols and the versa-
tility of epoxides as intermediates for biologically active
organosilicon compounds. The Si–O–Si bond could be
readily formed by the reaction of a Si–OH group on
the silica surface with organosilicon compounds. In this
letter, we report the grafting of poly-(L)-leucine on silica
´
´
target molecules. The Julia–Colonna asymmetric epoxi-
gel through the Si–O–Si bond and Julia–Colonna asym-
dation of a,b-unsaturated ketones, catalyzed by poly-
(amino acid) such as poly-(L)-leucine or poly-(L)-ala-
nine, is one of the most efficient methods for epoxidation
of electron-deficient substrates.1,2 In recent years, the
metric epoxidation of (E)-a,b-unsaturated aromatic
ketones catalyzed by the silica-grafted poly-(L)-leucine.
Grafting poly-(L)-leucine on silica gel was readily
effected as shown in Scheme 1. The silica functionalized
with primary 3-aminopropyl groups (AMPSi) was
prepared through the treatment with (3-amino-propyl)
triethoxysilane as reported in the literature.18,19
´
scope of the Julia–Colonna asymmetric epoxidation
has been extended largely including a,b-unsaturated
ketones, esters, and amides.3–12 However, the most serious
problem of the protocol is to handle the gel- or paste-
like catalyst. To circumvent this problem, poly(amino
acid) supported onto organic polymers through covalent
bonds13,14 or inorganic materials through simple physi-
cal absorption3,5,15,16 have been explored. However,
immobilization of poly(amino acid) on inorganic mate-
rials, such as silica gel, through covalent binding has
not been explored. Binding of an organic functional
group to silica surface via a covalent bond is the most
reliable method for modification and functionalization
of silica surface.17 The covalent bond used for the bind-
ing is mostly the Si–O–Si bond, where one of the silicon
atoms is on the silica surface and the other comes from
Polymerization of the amino acid N-carboxyanhydride
(NCA) using functionalized silica gel (AMPSi) as an
initiator was conducted in THF at room temperature
similar to the procedures used in the homogeneous
silica
gel
(EtO)3SiCH2CH2CH2NH2
toluene or EtOH
silica
gel
O
O
OH
OH
Si
OEt
NH2
AMPSi
O
O
O
H
silica
O
n
O
O
N
N
H
Si
N
R
n
H
gel
H
OEt
R
THF
R = CH2CH(CH3)2
Keywords: Asymmetric epoxidation; Grafted; Poly-(L)-leucine; a,b-
Unsaturated ketone.
(L-Leu)nAMPSi
*
Corresponding author. Tel.: +86 021 62232764; fax: +86 021
62232100; e-mail: jtang@chem.ecnu.edu.cn
Scheme 1. Preparation of poly-(L)-leucine-silica.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.096

5666
H. Yi et al. / Tetrahedron Letters 46 (2005) 5665–5668
system.20 Using this silica-grafted primary amine, AMP-
Si, as an initiator, N-carboxyanhydride (NCA) of L-leu-
cine were polymerized in THF, with AMPSi:NCA ratios
of 1:n at room temperature for 72 h under a nitrogen
atmosphere providing silica-grafted poly-(L-leucine),
(L-Leu)nAMPSi, with degrees of polymerization (n). A
series of the silica-grafted poly-(L)-leucine catalysts
were prepared with NCA of L-Leucine in THF using
AMPSi:NCA ratios of 1:6, 1:15, 1:30, and 1:45.
4) similar to the homogeneous catalyst. However, the
enantioselectivity of the reaction was independent on
the change of reaction conditions, such as oxidants
and solvents. Thus, almost the same enantioselectivities
and yields were obtained by using different protocols
(Table 2): a triphasic system, consisting of the insoluble
catalyst, a solution of the enone in toluene, and an aque-
ous layer containing H2O2 and NaOH (Table 2, entry 1);
the biphasic protocol, consisting of the insoluble catalyst
and a solution of the benzalacetophenone and DBU in
THF (Table 2, entry 2); or utilizing sodium percarbon-
ate as both oxidant and base, the percarbonate protocol
(Table 2, entries 3–5). Considering the ease of the cata-
lyst recovery and the reaction time, we chose the percar-
bonate protocol to further investigate oxidation of (E)-
a,b-unsaturated ketones with the poly-(L)-leucine-silica
catalysts.
The representative catalyst chosen for the characteriza-
tion was that with ratio AMPSi/NCA = 1:30. The infra-
red spectroscopy showed the characteristic absorption
of L-leucine at 3314, 2962, 2874, 1660, 1470, and
1440 cmÀ1 for the N–H, C–H, and C@O, respectively.1d
In the 13C CP-MAS NMR spectroscopy, signals at 173–
178, 50–60, 36–44, and 16–26 ppm were assigned to the
carbon atoms of poly-(L)-leucine. The peaks at 8.8, 20.5,
and 43.0 ppm in the 13C CP-MAS NMR spectroscopy
were attributed to the Si–C, Si–C–C, and Si–C–C–C–
N of the 3-aminopropyl groups, respectively.18,19 The
terminal amino groups, which were determined by
non-aqueous titration, were also in good agreement with
the number of amino groups of the initiator (AMPSi).
Reusability of the (L-Leu)nAMPSi catalyst in both
anhydrous and hydrous systems was also demonstrated
by the reactions using benzalacetophenone as the sub-
strate. The results are summarized in Tables 3 and 4,
respectively.
In the anhydrous system, the weight of the recovered cat-
alyst, (L-Leu)nAMPSi, increased with recycling while
enantioselectivity remarkably decreased due to the urea
adsorbed on the surface of the silica gel. However, after
the catalyst was washed with methanol, the catalytic
activity and enantioselectivity were retained (Table 3,
entry 5). In the hydrous system, the (L-Leu)nAMPSi cat-
alyst could be recycled several times, although the weight
of the recovered catalyst and the enantioselectivity of
The performance of the silica-grafted poly-(L)-leucine
catalyst in the oxidation of (E)-a,b-unsaturated ketones
was evaluated in the epoxidation of benzalacetophenone
under various conditions. The results are summarized in
Tables 1 and 2. In the model reaction of benzalaceto-
phenone epoxidation,21 the enantioselectivity increased
with the degrees of the polymerization of poly(L-
leucine), reaching 93% ee with n = 45 (Table 1, entry
Table 3. Reusability of the (L-Leu)nAMPSi catalyst in anhydrous
systema
Table 1. Asymmetric epoxidation of benzalacetophenone catalyzed by
(L-Leu)nAMPSi under different degrees of polymerizationa
Run
Catalyst (g)
Yield (%)
ee (%)
Entry
DFb
n
Yield (%)
ee (%)
1
2
3
4
5
0.70
0.80
0.89
0.99
0.65
90
93
92
90
93
93
82
78
56
93b
1
2
3
4
0.3
0.3
0.3
0.3
6
23
80
92
90
20
81
92
93
15
30
45
a General epoxidation procedure is described in Ref. 21.
b Degree of functionalization.
a Benzalacetophenone 1.2 mmol, catalyst, urea–H2O2 1.5 mmol, THF
3 ml, DBU 0.21 ml, ambient temperature, 6 h.
b The catalyst was washed with methanol after four times recycling.
Table 2. Asymmetric epoxidation of benzalacetophenone catalyzed by
(L-Leu)nAMPSi under different protocolsa
Table 4. Reusability of the (L-Leu)nAMPSi catalyst in hydrous
systema
Entry Oxidation/base
T
(h)
Solvent
Yield ee
(%) (%)
Run
Catalyst (g)
Yield (%)
ee (%)
1
0.50
0.49
0.49
0.48
0.47
0.47
0.46
0.45
0.44
0.43
94
92
93
90
83
80
78
80
78
83
93
90
91
89
86
85
83
82
82
80
1
2
3
4
5
H2O2/NaOHb
UHP/DBUc
48 Toluene 92
92
92
92
93
92
2
6
2
2
2
THF
92
93
93
94
d
3
Na2CO3Æ1.5H2O2
DME
DME
DME
H2O2/Na2CO3 (satd aq)e
H2O2/Na2CO3 (10% aq)e
4
5
6
a Benzalacetophenone 0.5 mmol, catalyst 0.04 mmol, ambient
temperature.
7
8
b Toluene 2 mL, H2O2 (30%) 0.5 mL, NaOH (10%) 0.25 mL.
c UHP 0.06 g (0.62 mmol), DBU 0.08 mL (0.53 mmol), anhydrous
THF 2 mL.
9
10
a 1.0 mmol benzalacetophenone, catalyst, 1.68 mmol sodium percar-
bonate, 2 ml DME, 2 ml H2O, ambient temperature, 2 h.
d Na2CO3Æ1.5H2O2 0.12 g (0.8 mmol), DME 1 mL.
e The solution of Na2CO3 1 mL, H2O2 0.1 mL, DME 1 mL.

H. Yi et al. / Tetrahedron Letters 46 (2005) 5665–5668
5667
Table 5. Enones epoxidized using the (L-Leu)nAMPSi catalysta
(d) Banfi, S.; Colonna, S.; Molinari, H. Tetrahedron 1984,
39, 5207–5211.
2. Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215–
1225.
3. Sylvia, B.; Karl, H. D.; Hans, P. K.; Stanley, M. R.; Jo¨rg,
S.; John, S.; Giampaolo, Z. Org. Process. Res. Dev. 2003,
7, 509–513.
4. Lauret, C.; Roberts, S. M. Aldrichim. Acta 2002, 35, 47–
51.
5. Geller, T. P.; Roberts, S. M. J. Chem. Soc., Perkin Trans.
1 1999, 1397–1398.
6. Porter, M. J.; Roberts, S. M.; Skidmore, J. Bioorg. Med.
Chem. 1999, 7, 2145–2156.
7. Falck, J. R.; Bhatt, R. K.; Reddy, K. M.; Ye, J. Synlett
1997, 481–482.
8. Allen, J. V.; Bergeron, S.; Griffiths, M. J.; Mukherjee, S.;
Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1998, 3171–
3179.
O
O
(L-Leu)nAMPSi
Oxidant
O
R1
Entry
R2
R1
R2
ee (%)
R1
Ph
R2
Yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
94
80
80
54
50
90
70
88
93
82
92
70
73
92
80
93
p-MeOC6H4
p-O2NC6H4
o-MeOC6H4
o-EtOC6H4
p-ClC6H4
Ph
Ph
Ph
Ph
Ph
o-MeOC6H4
p-ClC6H4
Ph
a 1.0 mmol substrate, 0.06 mmol catalyst, 1.6 mmol sodium percar-
bonate, 2 mLDME, 2 mL H2O, ambient temperature, 2 h.
9. Ray, P. C.; Roberts, S. M. Tetrahedron Lett. 1999, 40,
1779–1782.
10. Ebrahim, S.; Wills, M. Tetrahedron: Asymmetry 1997, 8,
3163–3173.
11. Pu, L. Tetrahedron: Asymmetry 1998, 9, 1457–1477.
12. Allen, J. V.; Roberts, S. M.; Williamson, N. M. Adv.
Biochem. Biotechnol. 1998, 63, 125–144.
epoxidation decreased with the recycling. Indeed, after 10
recycles a,b-epoxyketone was obtained in 83% yield in
80% ee under a constant condition (Table 4). The average
loss of catalyst amounted to ca. 1.4% per run.
The epoxidation of various (E)-a,b-unsaturated ketones
was examined using the silica-grafted poly(L-leucine).
All of the olefins tested afforded the corresponding
epoxides in good yields and enantioselectivities (Table
5). Electron-donating groups, such as MeO, decreased
the enantio-selectivity of the asymmetric epoxidation
significantly while electron-withdrawing ones showed
little effects (Table 5, entries 2, 3, and 6). Ortho-substit-
utents, namely steric hindrance, lowered both the yields
and enantioselectivities of the reactions catalyzed by the
silica-grafted poly-(L)-leucine (Table 5, entries 4, 5, and
7).
13. Itsuno, S.; Sakakura, M.; Ito, K. J. Org. Chem. 1990, 55,
6047–6049.
14. Cappi, M. W.; Chen, W. P.; Flood, R. W.; Liao, Y. W.;
Roberts, S. M.; Skidmore, J.; Smith, J. A.; Williamson, N.
M. Chem. Commun. 1998, 1159–1160.
15. Dhanda, A.; Drauz, K. H.; Geller, T.; Roberts, S. M.
Chirality 2000, 12, 313–317.
16. Carde, L.; Davies, H.; Geller, T. P.; Roberts, S. M.
Tetrahedron Lett. 1999, 40, 5421–5424.
17. Choong, E. S.; Sang-gi, L. Chem. Rev. 2002, 102, 3495–
3524.
18. Enrico, A.; Carlo, C.; Giovanni, M.; Paolo, V. J. Chem.
Soc., Perkin Trans. 1 1989, 105–107.
19. Anne, C.; Gilbert, R.; Daniel, B. J. Org. Chem. 1997, 62,
749–751.
In conclusion, we have developed a silica-grafted poly-
(L)-leucine that could act as an efficient chiral catalyst
in the epoxidation of (E)-a,b-unsaturated aromatic
ketones with the percarbonate protocol to yield optically
active epoxy ketones in high enantioselectivities up to
93% ee. Separation and recovery of the poly-(L)-leucine
catalyst has been remarkably improved in this system,
and the catalyst could be reused without a significant
loss of activity. The good substrate compatibility would
enable the synthesis of a variety of optically active epoxy
ketones.
20. Synthesis of silica-grafted poly(L-leucine) catalysts. The
AMPSi 3.2 g (0.3 mmol of NH2/g) was dried under
vacuum (0.5mmHg) at 110 °C for 2 h prior to use. The
AMPSi and L-leucine NCA (5.0 g, 32 mmol) were mixed
in anhydrous tetrahydrofuran (80 mL) at room tempera-
ture for 72 h with stirring. After stirring, the solid was
filtered, thoroughly washed with methanol (60 mL, stir-
ring 6 h) and diethyl ether (60 mL, stirring overnight) and
dried under vacuum at room temperature (6.6 g). IR
(cmÀ1) 3314, 2962, 2874, 1660, 1470, 1440, 1219, 1086,
963, 799, 465; 13C CP-MAS d (ppm) = 8.8, 20.5, 24.3, 39.4,
43.0, 55.9, 175.9. Anal. Calcd for C183H338N31O30@SiO2:
C, 32.67; N, 6.45. Found: C, 32.04; N, 6.21.
21. (a) Typical epoxidation procedure under a hydrous
condition:
Acknowledgments
To a solution of the enone (0.5 mmol) in DME (1 mL) and
H2O (1 mL) was added percarbonate (0.76 mmol) and the
grafting poly(L-leucine)-silica (0.04 mmol). The mixture
was stirred for 6 h at room temperature until the reaction
was completed (TLC). The catalyst was removed by rapid
filtration and washed with ethyl acetate. The combined
organic fractions were evaporated in vacuo to yield crude
epoxide;
We thank Shanghai Science and Technology Council
(04JC14032) and National Science Foundation of China
(20233030) for financial supports.
References and notes
´
1. (a) Julia, S.; Masana, J.; Vega, J. C. Angew. Chem., Int.
Ed. Engl. 1980, 19, 929–931; (b) Julia, S.; Guixer, J.;
(b) Typical epoxidation procedures under an anhydrous
condition:
´
Masana, J.; Rocas, J.; Colonna, S.; Annuziata, R.;
Molinari, H. J. Chem. Soc., Perkin Trans. 1 1982, 1317–
´
1324; (c) Colonna, S.; Molinari, H.; Banfi, S.; Julia, S.;
Masana, J.; Alvarez, A. Tetrahedron 1983, 39, 1635–1641;
A solution of the substrate (1.2 mmol) in anhydrous THF
were added urea–hydrogen peroxide (1.5 mmol), DBU
(1.5 mmol) and the grafting poly(L-leucine)-silica
(0.06 mmol). The mixture was stirred at room temperature

5668
H. Yi et al. / Tetrahedron Letters 46 (2005) 5665–5668
until the reaction was complete (TLC). The catalyst was
(c) The enantiomeric excess was determined by chiral-
phase HPLC analysis with a ChiralpakÒ AD column
(fluent: 10% i-PrOH in hexane, UV detection at 254
nm).
removed by rapid filtration and washed with ethyl acetate.
The combined organic fractions were evaporated in vacuo
to yield crude epoxide;