Synthesis of (αR,βS)-epoxyketones by asymmetric epoxidation of chalcones with cinchona phase-transfer catalysts

Article abstract of DOI:10.1016/j.tetlet.2010.08.056

An efficient method to synthetically produce optically enriched (αR,βS)-epoxyketones was developed using a quaternary ammonium salt derived from cinchona alkaloid as the chiral phase-transfer catalyst. (αR,βS)-Epoxyketones were prepared in high optical purities (91-99% ee) by the asymmetric epoxidation of 1,3-diarylenones with aqueous sodium hypochlorite in the presence of a hydrocinchonine-derived chiral phase-transfer catalyst bearing a 2,3,4-trifluorobenzyl group.

Full text of DOI:10.1016/j.tetlet.2010.08.056

Tetrahedron Letters 51 (2010) 5601–5603
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Tetrahedron Letters
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Synthesis of (
aR,bS)-epoxyketones by asymmetric epoxidation of chalcones
with cinchona phase-transfer catalysts
Mi-Sook Yoo a, Dong-Guk Kim b, Min Woo Ha a, Sang-sup Jew a, Hyeung-geun Park a, , Byeong-Seon Jeong b,
⇑
⇑
a College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method to synthetically produce optically enriched (
using a quaternary ammonium salt derived from cinchona alkaloid as the chiral phase-transfer catalyst.
a
R,bS)-epoxyketones was developed
Received 20 July 2010
Revised 13 August 2010
Accepted 18 August 2010
Available online 21 August 2010
(a
R,bS)-Epoxyketones were prepared in high optical purities (91–99% ee) by the asymmetric epoxidation
of 1,3-diarylenones with aqueous sodium hypochlorite in the presence of a hydrocinchonine-derived chi-
ral phase-transfer catalyst bearing a 2,3,4-trifluorobenzyl group.
Ó 2010 Elsevier Ltd. All rights reserved.
Enantiomerically enriched
a
,b-epoxyketones are considered ver-
In terms of the oxidant, hypochlorite5,7,10,13 including in situ gener-
ation from trichloroisocyanuric acid8 or hydroperoxide6,9,12,14/tert-
butylperoxide11 under basic conditions has been employed in most
reaction systems.
satile chiral building blocks in asymmetric organic synthesis and
medicinal chemistry.1 They can be converted to many types of useful
chiral compounds such as
nyls, ,b-dihydroxycarbonyls, epoxyalcohols, and b-ketoaldehy-
des.1 Asymmetric epoxidation of
,b-unsaturated ketones has
been the most widely used method for synthetically producing opti-
cally active
,b-epoxyketones.2 In the last two decades, considerable
a-hydroxycarbonyls, b-hydroxycarbo-
a
A class of the cinchona-PTCs containing a N-2,3,4-trifluoroben-
zyl moiety (4 and 5, Fig. 1), first introduced by us in 2002,15 has
been shown to possess excellent catalytic efficiency in the asym-
a
a
metric synthesis of optically active
a a-
-amino acid derivatives,16
efforts have been directed toward the asymmetric epoxidation of
enone, and the most well-established methods used for this reaction
include the use of chiral ligand-metal peroxides, polyamino acid,
chiral hydroperoxides, chiral dioxiranes, chiral pyrrolidines, or chi-
ral phase-transfer catalysts.2
Asymmetric phase-transfer catalysis has been extensively stud-
ied due to its many advantages including operational simplicity, no
need for anhydrous reaction conditions, and the high level of
asymmetric induction through the use of non-metallic catalyst,
and many highly effective reaction systems have been developed.3
Particularly, with regard to asymmetric phase-transfer-catalyzed
hydroxycarbonyls,17 and ,b-epoxysulfones.18 To demonstrate the
a
potential applicability of 4 and 5 in other asymmetric organic reac-
tions, here, we used these compounds in the asymmetric epoxida-
tion of chalcones 1.
These reactions were initiated using C(9)–O-allylated cinchona-
PTCs (G2 = allyl in Fig. 1) and sodium hypochlorite.19 Four basic
PTCs (4a, 4b, 5a, and 5b) were prepared from natural cinchona
alkaloids (cinchonidine for 4a, quinine for 4b, cinchonine for 5a,
and quinidine for 5b) in two sequential steps: N-quaternarization
with 2,3,4-trifluorobenzyl bromide followed by C(9)–O-allylation
with allyl bromide and KOH.15–18 The initial screening of the reac-
tion conditions was performed with trans-chalcone (1a,
Ar1 = Ar2 = Ph), 11% aqueous sodium hypochlorite (10 equiv) in
the presence of the prepared PTC (10 mol %) in toluene at room
temperature, and the results are summarized in Table 1. The four
basic PTCs (entries 1–4) all promoted the reaction under the given
conditions to exclusively produce trans-epoxide (2a + 3a). The
epoxidation of acyclic enones such as trans-chalcones
1
(Scheme 1), several efficient methods have been developed since
the first report by Wynberg and co-worker in 1978.4 Many types
of chiral phase-transfer catalysts (PTCs) have been applied to the
asymmetric epoxidation of 1, and fine tuning of the reaction condi-
tions with various oxidants has been performed. To date, cinchona
alkaloid-derived PTCs (cinchona-PTCs) have been the most widely
used PTCs by several groups including Lygo,5 Arai and Shioiri,6 Cor-
ey,7 Liang,8 and us.9 Besides the cinchona-PTCs, other useful chiral
PTCs have been developed for this epoxidation such as N-spiroam-
monium salts,10 azacrown ethers,11,12 and guanidinium salts.13,14
O
O
O
chiral PTC
−OX
(X = Cl, OH, OR)
O
O
+
Ar1
Ar2
Ar1
Ar2
Ar1
Ar2
β
β
α
α
1
2
3
(αR,βS)
(αS,βR)
⇑
Corresponding authors. Tel.: +82 2 880 7871; fax: +82 2 872 9129 (H.-g.P.); tel.:
+82 53 810 2814; fax: +82 53 810 4654 (B.-S.J.).
Scheme 1. Asymmetric epoxidation of chalcones 1 under phase-transfer catalytic
conditions.
E-mail addresses: hgpk@snu.ac.kr (H. Park), jeongb@ynu.ac.kr (B.-S. Jeong).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.056

5602
M.-S. Yoo et al. / Tetrahedron Letters 51 (2010) 5601–5603
G1
G3
N
Table 2
Tuning of reaction conditions
G1
G2
G3
N
X
F
X
O
N
8
9
4'
N
Br
F
O
F
F
N
3'
O
F
2'
N
G2
F
O
O
F
F
F
O
5c
Ph
Ph
Ph
Ph
4
5
NaOCl, toluene, temp.
(from cinchonidine or quinine)
(from cinchonine or quinidine)
1a
2a (αR,βS)
G1 = vinyl or ethyl; G2 = H, allyl or benzyl
G3 = H, or methoxy; X = Cl or Br
Entry Temp Equiv of NaOCla Mol % of 5c Time
Yield
(%)
ee (%)
(h)
1
2
3
4
5
6
7
8
9
rt
rt
rt
rt
10
10
10
5
10
5
2
5
5
10
5
5
4
4
10
8
40
24
48
50
48
96
95
91
97
90
72
82
81
80
78
80
79
80
85
85
91
87
83
G1
G2
G3
H
X
4a
4b
5a
5b
5c
vinyl allyl
vinyl allyl
vinyl allyl
vinyl allyl
ethyl allyl
Br
OMe Br
Br
OMe Br
Br
rt
2
0 °C
0 °C
0 °C
0 °C
10
10
5
H
H
2
10
a
Figure 1. N-2,3,4-Trifluorobenzyl-containing cinchona-PTCs.
11% Aqueous sodium hypochlorite was used, and consequently, the volume of
the aqueous layer in a biphasic system varied with the equivalent of sodium
hypochlorite.
Table 1
Initial screeninga
chiral PTC
NaOCl
toluene, rt
fraction of stereoisomers obtained in each case varied with the nat-
O
O
O
O
O
ure of the cinchona-PTC employed. PTCs 4 produced the (
epoxide (3a) as the major enantiomer, while significantly more
R,bS)-epoxide (2a) was obtained when PTCs 5 was used. The le-
aS,bR)-
+
Ph
Ph
Ph
Ph
Ph
Ph
1a
2a
3a
(a
(αR,βS)
(αS,βR)
vel of enantioselectivity was also affected by the PTC, where cin-
chonine-PTC 5a provided the highest enantioselectivity (76% ee)
among the four PTCs tested. Hydrocinchonine-PTC 5c led to a slight
increase in enantiomeric excess (78% ee, entry 5) and this PTC was
chosen to tune the other reaction parameters. Results obtained
from varying the reaction conditions (reaction temperature,
amount of the oxidant, and catalyst) are shown in Table 2.
Reactions at low temperature (0 °C, entries 6–9) generally re-
sulted in higher enantioselectivities than at room temperature (en-
tries 1–5) although the chemical yields were slightly lower at
longer reaction times. The amounts of sodium hypochlorite did
not seem to be closely related to chemical/optical yield. Notably,
the enantiomeric excess was maintained with a smaller quantity
of the catalyst 5c (entries 2 and 3), and even an enhanced enantio-
meric excess was observed at 0 °C (entry 7).20 The reaction condi-
tions shown in entry 7 in Table 2 were finally selected to
investigate the scope and limitations of this reaction.
Entry
PTC
Time (h)
Yieldb (%)
Major enantiomerc
eed (%)
1
2
3
4
5
4a
4b
5a
5b
5c
5
6
4
6
4
96
95
96
94
97
3a
3a
2a
2a
2a
63
26
76
57
78
a
The reaction was carried out with trans-chalcone (1a, 1.0 equiv) and 11%
aqueous sodium hypochlorite (10.0 equiv) in the presence of PTC (10 mol %) in
toluene at room temperature.
b
Yield of isolated product (2a + 3a).
The absolute configuration was determined by comparison of the HPLC reten-
c
tion time with the authentic sample independently synthesized by the reported
procedure.5b,6b,9
d
Enantiomeric excess was determined by HPLC analysis using a chiral column
(Chiralpak-AD) with hexanes/ethanol (volume ratio = 90:10) as the eluent; in this
case it was established by analysis of the racemate, of which the enantiomers (2a
and 3a) were fully resolved [flow rate: 1 mL/min, detection: 254 nm, retention
times: 17.7 min (2a), 25.7 min (3a)].
Table 3
Synthesis of (a
R,bS)-epoxyketones 2 via asymmetric phase-transfer catalytic epoxidation of chalcones 1a
5c (5 mol%)
11% NaOCl (10.0 equiv)
O
O
O
Ar1
Ar2
Ar1
2 (αR,βS)
Time (h)
Ar2
toluene, 0 ºC
1
Entry
Chalcones 1
Ar1
Ar2
Epoxides 2
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
4-Me-Ph
Naphthalene-2-yl
6-MeO-naphthalene-2-yl
4-MeO-Ph
Thiophene-2-yl
4-F-Ph
4-F-Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
48
48
48
40
40
40
24
48
40
16
48
2a
2b
2c
2d
2e
2f
2g
2h
2i
82
71
63
81
90
95
91
90
95
90
63
91
92
91
95
91
95
99
91
92
93
94
4-Cl-Ph
4-NO2-Ph
4-NO2-Ph
Naphthalene-2-yl
10
11
1j
1k
4-F-Ph
4-F-Ph
2j
2k
a
The reaction was carried out with trans-chalcone (1.0 equiv) and 11% aqueous sodium hypochlorite (10.0 equiv) in the presence of 5c (5 mol %) in toluene at 0 °C.
Yield of isolated product.
Enantiomeric excess was determined by HPLC analysis using a chiral column (Chiralpak-AD or Chiralcel-OD) with hexanes/ethanol or hexanes/2-propanol as the eluent
b
c
(flow rate: 1 mL/min, detection: 254 nm); in this case it was established by analysis of the racemate, of which the enantiomers were fully resolved.

M.-S. Yoo et al. / Tetrahedron Letters 51 (2010) 5601–5603
5603
11. (a) Bakó, T.; Bakó, P.; Keglevich, G.; Bombicz, P.; Kubinyi, M.; Pál, K.; Bodor, S.;
Makó, A.; Toke, L. Tetrahedron: Asymmetry 1589, 2004, 15; (b) Bakó, P.; Bakó, T.;
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As shown in Table 3, this epoxidation system was fairly effec-
tive in many cases for 1,3-diarylenones (chalcones 1).21 The epox-
idation proceeded smoothly within 16–48 h and produced the
}
Asymmetry 2005, 1861, 16; (d) Makó, A.; Rapi, Z.; Keglevich, G.; Szöllosy, Á.;
corresponding (aR,bS)-epoxyketones 2 with high enantioselectivi-
}
ties and good chemical yields.22 As mentioned above, many studies
have been devoted to the asymmetric epoxidation of enones using
cinchona-PTCs,4–9 but most of the methods developed have fo-
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Here we provide another efficient synthetic method for producing
a
S,bR)-enantiomers with the exception of one.5a
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(aR,bS)-epoxyketones 2 using the cinchona-PTC 5c.
In conclusion, we developed an efficient method for the synthe-
sis of optically enriched (aR,bS)-epoxyketones 2 from chalcones 1
via enantioselective phase-transfer catalytic epoxidation with so-
dium hypochlorite oxidant and the chiral cinchona-PTC 5c bearing
2,3,4-trifluorobenzyl moiety.
Acknowledgment
This work was supported by the Yeungnam University Research
Grants in 2008 (Grant No.: 208-A-235-257).
18. Ku, J.-M.; Yoo, M.-S.; Park, H.-g.; Jew, S.-s.; Jeong, B.-S. Tetrahedron 2007, 63,
8099.
References and notes
19. An interesting tendency can be found in the asymmetric epoxidation of
chalcones using cinchona-PTCs. A cinchona-PTC with free hydroxy group at
C(9) position generally provides better enantioselectivity when an alkaline
peroxide is used as the oxidant. On the other hand, a hypochlorite oxidant is
well suited for the C(9)-O-alkylated cinchona–PTC.5–8
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20. Use of C(9)-O-benzyl analog of 5c under the conditions of entry 7 in Table 2
gave the epoxide 2a at a chemical yield of 80% and 86% ee.
3. Maruoka, K. Asymmetric Phase Transfer Catalysis; Wiley-VCH Verlag GmbH & Co
KGaA: Weinheim, 2008.
21. Typical procedure: A mixture of trans-chalcone (1a, 35 mg, 0.17 mmol) and PTC
5c (4.8 mg, 8.5 lmol) in toluene (1 mL) was cooled at 0 °C. 11% Aqueous
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sodium hypochlorite solution (1.25 mL, 1.7 mmol) was then added to the
mixture, and the resulting mixture was stirred vigorously at 0 °C for 48 h. The
mixture was diluted with ethyl acetate (10 mL) and water (5 mL), and the
layers were separated. The aqueous layer was extracted with ethyl acetate
(10 mL Â 2). The combined organic layer was washed with brine, and dried
over MgSO4, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (hexanes/ethyl acetate = 50:1) to
give the epoxyketone 2a (31 mg, 82%) as a white solid. HPLC conditions:
Chiralpak AD, hexanes/ethanol = 90:10, 1 mL/min, 254 nm, tR = 17.7 min (2a),
25.7 min (3a), 91% ee.
22. The epoxidation of enones with alkyl or other non-phenyl groups attached to
carbonyl led to only modest enantioselection.