Enantioselective synthesis of heteroaromatic epoxyketones under phase-transfer catalysis using D-glucose- and D-mannose-based crown ethers

Article abstract of DOI:10.1016/j.tetasy.2011.07.001

Heteroaromatic epoxyketones have been synthesized in an asymmetric Darzens condensation of 2-chloroacetylfuran or 2- and 3-chloroacetylthiophene with aromatic aldehydes and in the enantioselective epoxidation of α,β-enones with an N-methylpyrrole unit, in

Full text of DOI:10.1016/j.tetasy.2011.07.001

Tetrahedron: Asymmetry 22 (2011) 1189–1196
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of heteroaromatic epoxyketones under
phase-transfer catalysis using D-glucose- and D-mannose-based crown ethers
a
a
a
b
c
a,
⇑
}
Zsolt Rapi , Tamás Szabó , György Keglevich , Áron Szöllosy , László Drahos , Péter Bakó
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, 1521 Budapest, Hungary
b Department of Inorganic and Analytical Chemistry, H-1525 Budapest, Hungary
c Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Heteroaromatic epoxyketones have been synthesized in an asymmetric Darzens condensation of 2-chlo-
roacetylfuran or 2- and 3-chloroacetylthiophene with aromatic aldehydes and in the enantioselective
Received 23 May 2011
Accepted 1 July 2011
Available online 4 August 2011
epoxidation of
or -mannose-based 2 crown ethers as phase transfer catalysts. The use of
as the catalyst gave the best results. The ,b-epoxyketones with a furan or a thiophene moiety were
a
,b-enones with an N-methylpyrrole unit, in both cases in the presence of
D-glucose- 1
D
D-glucose-based 1 lariat ether
a
obtained in good enantioselectivities (up to 86% ee) as well as excellent diastereoselectivities (up to
98:2), but the epoxyketones with a pyrrole-ring were formed in the Darzens condensation in low yields
and enantioselectivities. The epoxyketones with an N-methylpyrrole moiety isolated from the epoxida-
tion of the corresponding
to 81%) in the presence of catalyst 1 under mild reaction conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
a,b-enones were obtained in significant enantioselectivities (in ee values up
1. Introduction
while the trans-epoxides could be obtained in up to 43%
enantiomeric excess.4 Aggarwal et al. have developed a highly
enantioselective variation of the Darzens condensation to give
trans-glicidic amides by replacing the halide leaving group with a
chiral sulfonium salt.5 A simple method for the preparation of
chiral epoxides involves the Darzens condensation carried out
under phase transfer catalytic conditions in the presence of opti-
cally active catalysts. Arai et al. have used cinchona alkaloid deriv-
atives as chiral phase transfer catalysts for asymmetric Darzens
condensations, obtaining enantioselectivities of up to 86% using
While epoxides are important functional groups in organic syn-
thesis as targets in their own right, they are perhaps more impor-
tant as intermediates that yield bifunctional compounds after
stereoselective ring-opening with a nucleophile. Starting from an
enantiopure epoxide, the absolute stereochemistry at the two adja-
cent stereogenic centers can be controlled, and consequently epox-
ides not only have a long history as targets for asymmetric
catalysis, but a variety of enantioselective catalytic methods for
their synthesis also exists.1
cyclic a
-chloroketone substrates,6 up to 79% for reactions involving
Two essential methods are known for the preparation of
epoxy carbonyl compounds: the Darzens condensation and the
epoxidation of ,b-enones. Both methods can be also performed
under phase-transfer conditions.2
For the synthesis of ,b-epoxycarbonyls and related com-
a,b-
a
-chloroacetophenone,6,7 and up to 83% for reactions using chloro-
methyl phenyl sulfone.7 Recently, Arai et al. reported the use of a
synthetic bis-ammonium salt as an asymmetric phase transfer cat-
a
alyst for the Darzens condensation of N,N-diphenyl a-haloamides,
a
predominantly obtaining the cis-epoxides with up to 64% ee for the
pounds, one of the most powerful methodologies (one-step meth-
cis-epoxide, and up to 70% ee for the trans-epoxide.8
od) is the Darzens condensation between a carbonyl compound
Chiral monoaza-15-crown-5 type macrocycles incorporating an
a-D-glucopyranoside or an a-D-mannopyranoside unit 1 and 2
and an
a
-halo-carbonyl compound (or related species).3 Recently,
progress has been made in developing asymmetric variants of this
epoxide synthesis.
were synthesized in our laboratory, and proved to be efficient cat-
alysts in a few asymmetric reactions.9 The Darzens condensation
North et al. used a cobalt(salen) complex to catalyze the asym-
between the benzaldehyde and a-chloroacetophenone was
metric Darzens condensation of
cis-epoxides could be obtained in up to 50% enantiomeric excess,
a
-haloamides and aldehydes. The
achieved with up to 72% ee in the presence of catalyst 1 (see
Fig. 1).10
Herein we report the asymmetric Darzens condensation of some
heteroaromatic chloromethyl ketones with various aromatic alde-
hydes (there was no asymmetric induction with the aliphatic alde-
hydes). Our preliminary results concerning the enantioselective
⇑
Corresponding author.
E-mail address: pbako@mail.bme.hu (P. Bakó).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.001

1190
Z. Rapi et al. / Tetrahedron: Asymmetry 22 (2011) 1189–1196
Table 1
OCH3
OCH3
O
O
O
O
Asymmetric Darzens condensation of 2-chloroacetylfuran 4 with aromatic aldehydes
in the presence of catalyst 1 at ꢀ5 °C
O
O
O
O
O
O
N
(CH2)3OH
N
(CH2)3OH
Yielda (%)
eec (%)
½ ꢁ
a 2D2
b
Entry
Ar
Time (h)
1
2
3
4
5
6
Ph
8
12
5
3
3
5a: 55
5b: 64
5c: 77
5d: 67
5e: 45
5f: 30
ꢀ117.7
ꢀ33.1
54d
57 (84)
70 (91)
62
64
28
O
O
O
O
2-H3C-C6H4
2-Cl-C6H4
4-Cl-C6H4
Piperonyl
2-Naphthyl
ꢀ14.9
ꢀ146.5
ꢀ151.3
ꢀ73.6
1
2
1
a
b
c
Figure 1. Crown ethers containing an
ranoside 2 unit.
a-
D-glucopyranoside 1 or an
a
-D
-mannopy-
Based on preparative TLC.
In CH2Cl2, c 1.
Determined by 1H NMR spectroscopy, the ee given in the parentheses was
obtained after one recrystallization from EtOH.
Darzens reactions using catalysts 1 and 2 have already been
d
reported.11
Ref. 14.
2. Results and discussion
O
crown cat.
Cl
+
ArCHO
2.1. Darzens condensation
Ar
S
toluene
30 % NaOH
S
O
O
The starting 2-chloroacetylfuran, 2-chloroacetylthiophene and
3-chloroacetylthiophene were prepared by the selective
3
6
7
a-
chlorination of the corresponding acetyl derivatives by benzyl-
trimethylammonium dichloroiodate in dichloroethane/methanol,12
or in the case of the 2-chloroacetylpyrrole and 2-chloroacetyl-N-
methylpyrrole in a tetrahydrofuran solution.13
Scheme 2.
Table 2
Asymmetric Darzens condensation of 2-chloroacetylthiophene
aldehydes in the presence of catalyst 1 at ꢀ5 °C
6
with aromatic
eec (%)
The Darzens reactions were carried out in a liquid–liquid two-
phase system in toluene, employing 30% aq NaOH as the base
and 7 mol % of chiral crown catalysts 1 and 2 at a temperature of
ꢀ5 °C. The products were isolated by preparative TLC. The trans-
epoxyketones were obtained in all experiments in a diastereomeric
excess (de) of >98%. The asymmetric induction expressed in the
terms of the enantiomeric excess (ee) was determined by 1H
NMR analysis in the presence of Eu(hfc)3 as a chiral shift reagent.
First, the reaction of 2-chloroacetylfuran 4 and substituted benzal-
dehydes 3 was studied (Scheme 1). Experimental data are listed in
Table 1.
Yielda (%)
½ ꢁ
a 2D2
b
Entry
Ar
Time (h)
1
2
3
4
5
6
7
8
9
Ph
5
4.5
6
20
22
3
5
6
5
7a: 63
7b: 53
7c: 56
7d: 54
7e: 55
7f: 79
7g: 87
7h: 54
7i: 57
ꢀ169.8
ꢀ10.0
71 (84)d
51
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
2-H3C-C6H4
1-Naphthyl
2-Naphthyl
Piperonyl
ꢀ142.1
ꢀ139.0
ꢀ119.7
ꢀ45.7
60 (75)
65 (79)
62 (73)
68 (85)
64 (75)
62
+54.0
ꢀ163.0
ꢀ131.5
86 (100)
a
b
c
Based on preparative TLC.
In CH2Cl2, c 1.
O
Determined by 1H NMR spectroscopy, the ee given in parentheses was obtained
crown cat.
Cl
+
ArCHO
after one recrystallization from EtOH.
Ar
O
toluene
30 % NaOH
d
O
Ref. 15.
O
O
3
4
5
ues of 51–68% (Table 2, entries 2–6). In the substituted series,
2-methylbenzaldehyde gave the best enantiomeric purity (68%
ee). After recrystallization, the enantiomeric purity was increased
to 85% (entry 6). The degree of asymmetric induction was affected
by the position of the chloro atom in the benzaldehyde: 2-Cl-, 3-Cl-
and 4-Cl derivatives 7b, 7c, 7d) were formed with 51%, 60% and
65% ee, respectively. It was observed, that the further the chloro
atom was situated from the reaction center, the greater the extent
of asymmetric induction, that is, the best ee (65% ee) was obtained
with p-chlorobenzaldehyde (entry 4). It is worth mentioning that
the use of 1-naphthaldehyde and 2-naphthaldehyde led to prod-
ucts 7g and 7h with opposite specific rotations, but approximately
the same ee value (entries 7 and 8). The reaction of 2-chloroacetyl-
thiophene with piperonal gave the best enantioselectivity (86%).
Moreover, after completion of the reaction, nearly half of the
epoxyketone 7i precipitated from the mixture as a pure enantio-
mer (100% ee).
Scheme 1.
The trans-epoxyketones 5a–f had negative specific rotation val-
ues and were obtained in yields of 30–77%. The reaction of 4 with
benzaldehyde gave the (2R,3S)-epoxyketone 5a in an enantiomeric
excess of 54%.14 The use of substituted benzaldehydes led to higher
ee values that were dependent on the nature of the substitution
pattern of the phenyl ring (57–70%). The o-methyl product 5b
and the p-chloro derivative 5d were obtained with an ee of 57%
and 62%, respectively (entries 2 and 4). The maximum selectivity
was detected in the reaction of 2-chlorobenzaldehyde and epoxide
5c was formed in 70% (entry 3). The recrystallization of epoxyke-
tones 5b and 5c from ethanol resulted in higher ee’s of 84% and
91%, respectively. The reaction of 4 with piperonal took place with
an enantioselectivity of 64% (entry 5). The lowest ee value (28%)
was detected in the reaction with 2-naphthaldehyde (entry 6).
A reverse trend was observed for the phase-transfer catalyzed
To the best of our knowledge, only Arai et al. have reported high
Darzens reaction of 2-chloroacetyl-thiophene
Table 2).
In the reaction of 2-chloroacetylthiophene 6 with benzalde-
hyde, the (2R,3S) antipode of product 7a was formed in 71% ee.15
The reaction of substituted benzaldehydes provided lower ee val-
6
(Scheme 2,
enantioselectivities of up to 86% ee for the reaction of cyclic a-
chloroketones and aldehydes in the presence of a cinchonine deriv-
ative after prolonged (80–200 h) reaction times.6
In the reactions shown in Schemes 2 and 3, the mannose-based
crown ether 2 generated lower enantioselectivities when using

Z. Rapi et al. / Tetrahedron: Asymmetry 22 (2011) 1189–1196
1191
O
lectivities variable (16–51% ee, Table 4, entries 1–4). The best result
was achieved with 1-naphthaldehyde, and product 12c (Ar = 1-
naphthyl) obtained in 51% ee could be purified by repeated recrys-
tallization to afford suitable crystals. The absolute configuration
was found to be (2R,3S) after single crystal X-ray analysis.11
The low yields and ee values were attributed to side reactions
under basic conditions arising from the acidity of the NH moiety
of the pyrrole (entries 1–4). For this, experiments were carried
out with N-methyl-2-chloroacetylpyrrole 11 (Scheme 4), but in
reactions with benzaldehyde and o-chlorobenzaldehyde only the
yields were improved, while the ee values remained low (16%
and 19% ee, Table 4, entries 5 and 6).
crown cat. 1
Cl
S
+
ArCHO
S
Ar
toluene
30 % NaOH
O
O
3
8
9
Scheme 3.
Table 3
Asymmetric Darzens condensation of 3-chloroacetylthiophene
aldehydes in the presence of catalyst 1 at ꢀ5 °C
8
with aromatic
eec (%)
Yielda (%)
[a]
D
b
Entry
Ar
Time (h)
1
2
3
Ph
4
3
4
9a: 53
9b: 51
9c: 66
ꢀ72.2
ꢀ19.3
+51.9
52 (66)
52 (85)
54
2.2. Synthesis of chiral epoxides with an N-methylpyrrole
moiety by epoxidation of a,b-enones
2-H3C-C6H4
1-Naphthyl
a
b
c
Based on preparative TLC.
Following the unsuccessful Darzens conditions, the epoxyke-
tones with N-methylpyrrole moieties were prepared by the epoxi-
In CH2Cl2, c 1.
Determined by 1H NMR spectroscopy, the ee given in parentheses was obtained
dation of the corresponding
a,b-enones. In the first step, the
after one recrystallization from EtOH.
unsaturated ketones were synthesized, then oxidized in the pres-
ence of a chiral catalyst.
Many methodologies have been developed regarding asymmet-
ric epoxidation.1,2 A variety of catalytic asymmetric epoxidations of
electron-deficient olefins, in particular a,b-unsaturated ketones
have been published involving the use of hydrogen peroxide, alkyl-
peroxides, tert-butyl hydroperoxide or sodium and potassium
hypochlorites, as the oxidative agents, in the presence of various
polyaminoacids, chinchona alkaloids, chiral platinium(II) com-
plexes, lanthanoid–binaphthol complexes and chiral quaternary
ammonium salts as the phase transfer catalysts, or various organ-
ocatalysts, and so on.1,2,16
O
crown cat.
Cl
+
ArCHO
Ar
N
R
toluene
30 % NaOH
N
R
O
O
3
10
11
12
13
R = H
R = H
R = CH3
R = CH3
Scheme 4.
We have described the asymmetric epoxidation of a variety of
chalcone derivatives with tert-butyl hydroperoxide under phase
transfer catalytic conditions in the presence of azacrown 1 or 2.17
We wished to study the epoxidation of unsaturated ketones con-
taining an N-methylpyrrole unit in the presence of catalysts 1
and 2.
The starting ketones 15 were prepared by the condensation of
corresponding aromatic aldehydes 3 with 2-N-methylacetylpyrrole
14 in ethanol, in the presence of 10% KOH/H2O. Compounds 15a–i
were obtained in variable yields (37–86%, Scheme 5).
Table 4
Asymmetric Darzens condensation of 2-chloroacetylpyrrole 10 and 2-chloroacetyl-N-
methylpyrrole 11 with aromatic aldehydes in the presence of catalyst 1 at ꢀ5 °C
Yielda (%)
[a
]
D
eec (%)
b
Entry
R
Ar
Time (h)
1
2
3
4
5
6
H
H
H
H
CH3
CH3
Ph
0.8
0.5
0.8
2.5
5
12a: 33
12b: 28
12c: 22
12d: 29
13a: 72
13b: 59
ꢀ77.3
ꢀ1.2
36
20
51 (64)
18
16
2-CH3-C6H4
1-Naphthyl
2-Naphthyl
Ph
+24.9
ꢀ40.0
ꢀ41.5
ꢀ2.9
2-Cl-C6H4
4.5
19
a
b
c
Based on preparative TLC.
In CHCl3, c 1.
96% EtOH
Ar
Determined by 1H NMR spectroscopy, the ee given in parentheses was obtained
CH3
+
ArCHO
N
N
after one recrystallization from EtOH.
10% KOH
r.t
O
O
CH3
CH3
3
14
15
benzaldehyde. The products 5a and 7a (both with positive specific
rotations) were obtained in ee of 42% and 59%, respectively.
Repeated recrystallization of products 7f and 7i led to pure
enantiomers whose absolute configurations were determined by
single crystal X-ray analysis. In both cases, the configurations of
the stereogenic carbon atoms were found to be (2R,3S).11 The
phase transfer catalyzed Darzens reactions of 3-chloroacetylthi-
ophene were also investigated (Scheme 3).
It can be seen from the data in Table 3 that the substitution pat-
tern of the thiophene ring also influenced the extent of the asym-
metric induction: the reaction of 3-chloroacetylthiophene with a
few aromatic aldehydes (benzaldehyde, 2-methylbenzaldehyde
and 1-naphthaldehyde) took place with lower enantioselectivities
(52%, 52% and 54%), in the presence of catalyst 1, as compared to
the reaction of 2-chloroacetylthiophene (71%, 68%, 64%) and the
asymmetric induction was found to be not dependent on the nat-
ure of the substituents.
Scheme 5.
In our experiments, the epoxidation of ketones 15 with tert-
butylhydroperoxide (TBHP, 2 equiv) was carried out in a liquid–
liquid two-phase system employing toluene, 20% aq NaOH
(3.5 equiv) and 7 mol % of a chiral crown catalyst at room temper-
ature (Scheme 6). In most cases, the reactions were complete after
46–240 h. After the usual work-up, the product was isolated by
preparative TLC. The asymmetric induction, expressed in terms of
the enantiomeric excess (ee%), was determined by 1H NMR
crown cat.
t-BuOOH
O
Ar
Ar
toluene
20 % NaOH
N
N
O
O
CH3
CH3
Analogous reactions between aromatic aldehydes and 2-chloro-
acetylpyrrole 10 were carried out under similar conditions
(Scheme 4), but the yields were low (22–33%) and the enantiose-
13a-i
15a-i
Scheme 6.

1192
Z. Rapi et al. / Tetrahedron: Asymmetry 22 (2011) 1189–1196
Table 5
the mannose-based crown 2 enhanced the predominant formation
of the enantiomer with a positive specific rotation.
Asymmetric epoxidation of unsaturated ketones containing an N-methylpyrrole unit
15a–i in the presence of catalyst 1 at 22 °C
Entry
Ar
Time (h)
Yielda (%)
eec (%)
½ ꢁ
a 2D2
b
4. Experimental
4.1. General
1
2
3
4
5
6
7
8
9
Ph
46
100
122
240
160
68
48
168
52
13a: 80
13b: 73
13c: 88
13d: 92
13e: 83
13f: 79
13g: 83
13h: 72
13i: 69
ꢀ209.5
ꢀ7.0
79
51
79
81
65
70
79
70
77
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-H3C-C6H4
3-H3C-C6H4
4-H3C-C6H4
1-Naphthyl
2-Naphthyl
ꢀ207.0
ꢀ211.4
ꢀ49.7
Melting points were taken on using a Büchi 510 apparatus and
are uncorrected. Optical rotations were measured with a Perkin–
Elmer 241 polarimeter at 22 °C. 1H and 13C NMR spectra were re-
corded on a Bruker 300 and a Bruker DRX-500 or a Varian Inova
500 instrument in CDC13 with TMS as the internal standard. Ana-
lytical and preparative thin layer chromatography was performed
on silica gel plates (60 GF-254, Merck), while column chromatogra-
phy was carried out using 70–230 mesh silica gel (Merck). Chem-
icals and the shift reagent Eu(hfc)3 were purchased from Aldrich
Chem. Co. The exact mass measurements were performed using
Q-TOF Premier mass spectrometer (Waters Corporation, 34 Maple
St, Milford, MA, USA) in positive electrospray ionization mode. The
melting points of the epoxyketones were determined after crystal-
lization from ethanol.
ꢀ196.8
ꢀ216.3
+88.0
ꢀ219.7
a
b
c
Based on preparative TLC.
In CHCl3, c 1.
Determined by 1H NMR spectroscopy.
spectroscopy using (+)-Eu(hfc)3 as the chiral shift reagent. The
trans-epoxyketones were obtained in all experiments in a high dia-
stereoselectivity (de >98%). The results of the epoxidations are
shown in Table 5.
The oxidation reaction of unsaturated ketones catalyzed by
crown ether 1 afforded the corresponding epoxides 13a–i in excel-
lent diastereoselectivity (de >98%), in moderate to good yields and
in an enantioselectivity that was highly dependent on the nature of
the substituents and on their positions on the phenyl ring. The
epoxidation of compound 15a (Ar = Ph) took place with an ee of
79% (Table 5. entry 1). The 2-chloro-, 3-chloro- and 4-chlorophenyl
epoxyketones were obtained in 51%, 79% and 81% ee values,
respectively (Table 5, entries 2–4), while the 2-methyl-, 3-methyl-
and 4-methyl-derivatives were obtained in 65%, 70% and 79%
enantioselectivities, respectively (entries 5–7). It can be seen that
the further the substituent was located from the reaction center,
the more considerable the asymmetric induction. This suggests
the role of steric hindrance. It is worth noting that while in the
epoxidation of 2-naphthyl-derivative 15i (Ar = 2-naphthyl)
epoxyketone 13i was obtained with a negative specific rotation
(77% ee); the reaction of 1-naphthyl-derivative 15h led to product
13h with a positive specific rotation (70% ee).
4.2. General procedure for the Darzens condensation
A
toluene solution (3 mL) of aromatic a-chloro-ketone
(1.87 mmol), aromatic aldehyde (2.8 mmol) and the crown ether
(0.14 mmol) was cooled to ꢀ5 °C, and treated with 30% NaOH
(1 mL). The mixture was stirred at this temperature, until comple-
tion of the reaction (1–22 h), after which toluene (7 mL) and water
(3 mL) were added and the mixture was stirred for 10 min. The or-
ganic phase was washed with cold 10% HCl (3 ꢂ 10 mL) and water
(20 mL), dried (Na2SO4 and Na2CO3) and concentrated. The crude
product was purified on silica gel by preparative TLC with hex-
ane–EtOAc (10:1) as the eluent. The enantioselectivities were
determined by 1H NMR spectroscopy in the presence of Eu(hfc)3
as the chiral shift reagent.
The configuration of the major enantiomer of compounds 5a
and 7a were determined by comparison with the literature
data;14,15 for epoxyketones 7f, 7i and 12c, the configuration was
determined by single crystal X-ray analysis.11
The use of mannose-based macrocycle 2 led to a smaller extent
of asymmetric induction as compared to that of the glucose-based
1. For example, the epoxyketones 13d and 13g were obtained in
72% and 70% ee in the presence of catalyst 2. The antipode with
a positive specific rotation was formed in excess.
4.2.1. (2R,3S)-2,3-Epoxy-1-(2-furyl)-3-phenylpropan-1-one 5a
Yield: 55%; ½a 2D2
¼ ꢀ117:7 (c 1, CHCl3) 54% ee; mp 44–47 °C
ꢁ
{lit.14b
½
a 2D6
ꢁ
¼ ꢀ190 (c 1, CHCl3) 87% ee}; 1H NMR (CDCl3,
500 MHz) d (ppm): 7.68 (d, J = 1.5 Hz, 1H), 7.45 (d, J = 3.5 Hz, 1H),
7.39–7.36 (m, 3H), 7.35–7.33 (m, 2H), 6.59 (dd, J = 3.5 Hz, 1.5 Hz,
1H), 4.15 (d, J = 1.5 Hz, 1H), 4.14 (d, J = 1.5 Hz, 1H). HRMS calcd
for C13H10O3 214.0630, found 214.0628.
3. Conclusion
The glucose-based crown ether 1 induced a greater extent of
asymmetric induction both in Darzens condensation and epoxida-
tion as compared to mannose-based 2. In the Darzens condensa-
4.2.2. trans-(ꢀ)-2,3-Epoxy-1-(2-furyl)-3-(2-tolyl)-propan-1-one
tion of 2-chloroacetylfuran 4, 2-chloroacetylthiophene
6 and
5b
3-chloroacetyl-thiophene 8 28–70%, 51–86% and 52–54% ee values
were measured, respectively, in the presence of catalyst 1. In the
case of 2-substituted derivatives 4 or 6 the enantioselectivity de-
pended strongly on the substitution pattern of the benzaldehyde
reagent. In the case of 3-substituted compound 8, there was no
such dependence. The epoxyketones containing a pyrrole and an
N-methylpyrrole moiety 12a–d and 13a–b were obtained in poor
yields and low enantioselectivities in the Darzens condensation,
Yield: 64%; ½a 2D2
ꢁ
¼ ꢀ33:1 (c 1, CHCl3) 57% ee; mp 86 °C; 1H NMR
(CDCl3, 300 MHz) d (ppm): 7.69 (d, J = 1.5 Hz, 1H), 7.49–7.46 (m,
1H), 7.32–7.28 (m, 1H), 7.27–7.22 (m, 2H), 7.20–7.16 (m, 1H),
6.61 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 4.27 (d, J = 1.5 Hz, 1H), 4.04 (d,
J = 1.5 Hz, 1H), 2.36 (s, 3H). HRMS calcd for C14H12O3 228.0786,
found 228.0789.
4.2.3. trans-(ꢀ)-2,3-Epoxy-1-(2-furyl)-3-(2-chlorophenyl)-
but the epoxidation of the corresponding
a,b-enones gave the
propan-1-one 5c
products 13a–i in much better yields and ee values (51–81% ee).
The monosaccharide unit of the catalyst was decisive with respect
to the configuration of the epoxyketone formed. The glucose-based
catalyst 1 mostly promoted the formation of the (2R,3S)-enantio-
mer with a negative specific rotation (except the 1-naphthyl-
derivatives were formed with a positive specific rotation), while
Yield: 77%; ½a 2D2
ꢁ
¼ ꢀ14:9 (c 1, CHCl3, 70% ee); mp 82–85 °C; 1H
NMR (CDCl3, 300 MHz) d (ppm): 7.69 (d, J = 1.5 Hz, 1H), 7.47 (d,
J = 3.5 Hz, 1H), 7.40–7.28 (m, 4H), 6.61 (dd, J = 3.5 Hz, 1.5 Hz, 1H),
4.48 (d, J = 1.5 Hz, 1H), 4.03 (d, J = 1.5 Hz, 1H). HRMS calcd for
C13H9ClO3 248.0240, found 248.0243.

Z. Rapi et al. / Tetrahedron: Asymmetry 22 (2011) 1189–1196
1193
4.2.4. trans-(ꢀ)-2,3-Epoxy-1-(2-furyl)-3-(4-chlorophenyl)-prop-
1H), 4.16 (d, J = 1.5 Hz, 1H), 4.03 (d, J = 1.5 Hz, 1H). HRMS calcd
for C13H9FO2S 248.0307, found 248.0311.
an-1-one 5d
Yield: 67%; ½a 2D2
¼ ꢀ146:5 (c 1, CHCl3) 62% ee; mp 102–103 °C;
ꢁ
1H NMR (CDCl3, 500 MHz) d (ppm): 7.68 (d, J = 1.5 Hz, 1H), 7.45 (d,
J = 3.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.60
(dd, J = 3.5 Hz, 1.5 Hz, 1H), 4.13 (d, J = 1.5 Hz, 1H), 4.10 (d,
4.2.12. (2R,3S)-2,3-Epoxy-1-(2-thienyl)-3-(2-tolyl)-propan-1-
one 7f
Yield: 79%; ½a 2D2
ꢁ
¼ ꢀ45:7 (c 1, CH2Cl2) 68% ee; mp 72–74 °C; 1H
J = 1.5 Hz, 1H). HRMS calcd for
C
13H9ClO3 248.0240, found
NMR (CDCl3, 500 MHz), d (ppm): 8.03 (dd, J = 4 Hz, 1 Hz, 1H), 7.75
(dd, J = 5 Hz, 1 Hz, 1H), 7.30 (dd, J = 7 Hz, 2 Hz, 1H), 7.27–7.23 (m,
2H), 7.19 (t, J = 4.5 Hz, 1H), 7.18–7.17 (m, 1H), 4.29 (d, J = 1.5 Hz,
1H), 3.98 (d, J = 1.5 Hz, 1H), 2.37 (s, 3H). HRMS calcd for
248.0242.
4.2.5. trans-(ꢀ)-2,3-Epoxy-1-(2-furyl)-3-pyperonyl-propan-1-
one 5e
C14H12O2S 244.0558, found 244.0563.
Yield: 45%; ½a 2D2
ꢁ
¼ ꢀ151:3 (c 1, CHCl3) 64% ee; mp 82–84 °C; 1H
NMR (CDCl3, 300 MHz) d (ppm): 7.67 (d, J = 1.5 Hz, 1H), 7.45 (d,
J = 3.5 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H),
6.77 (s, 1H), 6.60 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 5.99 (s, 2H), 4.09 (d,
J = 1.5 Hz, 1H), 4.07 (d, J = 1.5 Hz, 1H). HRMS calcd for C14H10O5
258.0528, found 258.0525.
4.2.13. trans-(+)-2,3-Epoxy-1-(2-thienyl)-3-(1-naphthyl)-prop-
an-1-one 7g
Yield: 87%; ½a 2D2
ꢁ
¼ þ54 (c 1, CH2Cl2) 64% ee; mp 108–110 °C; 1H
NMR (CDCl3, 300 MHz), d (ppm): 8.03 (d, J = 3.5 Hz, 1H), 8.01–7.99
(m, 1H), 7.92–7.89 (m, 1H), 7.86 (d, J = 8 Hz, 1H), 7.77 (dd, J = 5 Hz,
1 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54–7.51 (m, 2H), 7.49 (d,
J = 7.5 Hz, 1H), 7.19 (t, J = 4.5 Hz, 1H), 4.80 (d, J = 1.5 Hz, 1H), 4.11
(d, J = 1.5 Hz, 1H). HRMS calcd for C17H12O2S 280.0558, found
280.0554.
4.2.6. trans-(ꢀ)-2,3-Epoxy-1-(2-furyl)-3-(2-naphthyl)-propan-1-
one 5f
Yield: 30%; ½a 2D2
¼ ꢀ73:6 (c 1, CHCl3) 28% ee; mp 114–117 °C;
ꢁ
1H NMR (CDCl3, 500 MHz) d (ppm): 7.88–7.82 (m, 4H), 7.67 (d,
J = 1.5 Hz, 1H), 7.53–7.50 (m, 2H), 7.47 (d, J = 3.5 Hz, 1H), 7.38
(dd, J = 8.5 Hz, 1.5 Hz, 1H), 6.59 (dd, J = 3.5 Hz, 1.5 Hz, 1H), 4.32
(d, J = 1.5 Hz, 1H), 4.24 (d, J = 1.5 Hz, 1H). HRMS calcd for
4.2.14. trans-(ꢀ)-2,3-Epoxy-1-(2-thienyl)-3-(2-naphthyl)-prop-
an-1-one 7h
Yield: 54%; ½a 2D2
ꢁ
¼ ꢀ163 (c 1, CH2Cl2) 62% ee; Oil; 1H NMR
C17H12O3 264.0786, found 264.0784.
(CDCl3, 500 MHz), d (ppm): 8.02 (d, J = 3 Hz, 1H), 7.90–7.82 (m,
4H), 7.75 (d, J = 4.8 Hz, 1H), 7.54–7.79 (m, 2H), 7.38 (d, J = 8.7 Hz,
1H), 7.18 (t, J = 4.2 Hz, 1H), 4.34 (d, J = 1.5 Hz, 1H), 4.18 (d,
4.2.7. trans-(ꢀ)-2,3-Epoxy-1-(2-thienyl)-3-phenylpropan-1-one
7a
J = 1.5 Hz, 1H). HRMS calcd for C17H12O2S 280.0558, found
280.0561.
Yield: 63%; ½a 2D2
ꢁ
¼ ꢀ169:8 (c 1, CH2Cl2) 71% ee; mp 49–50 °C; 1H
NMR (CDCl3, 500 MHz), d (ppm): 8.00 (d, J = 3.5 Hz, 1H), 7.73 (d,
J = 5 Hz, 1H), 7.39–7.37 (m, 3H), 7.35–7.33 (m, 2H), 7.17 (t,
J = 4.5 Hz, 1H), 4.17 (d, J = 1.5 Hz, 1H), 4.07 (d, J = 1.5 Hz, 1H). HRMS
calcd for C13H10O2S 230.0402, found 230.0406.
4.2.15. (2R,3S)-2,3-Epoxy-1-(2-thienyl)-3-piperonyl-propan-1-
one 7i
Yield: 57%; ½a 2D2
¼ ꢀ131:5 (c 1, CH2Cl2) 86% ee; After crystalliza-
ꢁ
tion: ½a 2D2
ꢁ
¼ ꢀ268:8 (c 1, CH2Cl2) 100% ee; mp 108–110 °C; 1H NMR
4.2.8. trans-(ꢀ)-2,3-Epoxy-1-(2-thienyl)-3-(2-chlorophenyl)-
(CDCl3, 500 MHz), d (ppm): 8.00 (d, J = 4 Hz, 1H), 7.74 (d, J = 5 Hz,
1H), 7.17 (t, J = 4.5 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.80 (d,
J = 8.1 Hz, 1H), 6.77 (s, 1H), 5.98 (s, 2H), 4.09 (d, J = 1.5 Hz, 1H),
4.02 (d, J = 1.5 Hz, 1H). HRMS calcd for C14H10O4S 274.0300, found
274.0306.
propan-1-one 7b
Yield: 53%; ½a 2D2
ꢁ
¼ ꢀ10 (c 1, CH2Cl2) 51% ee; mp 49–50 °C; 1H
NMR (CDCl3, 300 MHz), d (ppm): 8.02 (d, J = 3 Hz, 1H), 7.76 (d,
J = 4.8 Hz, 1H), 7.29–7.21 (m, 4H), 7.19 (t, J = 3.9 Hz, 1H), 4.49 (d,
J = 1.5 Hz, 1H), 3.97 (d, J = 1.5 Hz, 1H). HRMS calcd for C13H9ClO2S
264.0012, found 264.0008.
4.2.16. trans-(ꢀ)-2,3-Epoxy-1-(3-thienyl)-3-phenylpropan-1-
one 9a
4.2.9. trans-(ꢀ)-2,3-Epoxy-1-(2-thienyl)-3-(3-chlorophenyl)-
Yield: 53%; ½a 2D2
ꢁ
¼ ꢀ72:2 (c 1, CH2Cl2) 52% ee; mp 91–93 °C; 1H
propan-1-one 7c
NMR (CDCl3, 500 MHz), d (ppm): 8.37 (dd, J = 2.5 Hz, 1 Hz, 1H),
7.65 (dd, J = 5 Hz, 1 Hz, 1H), 7.40 (dd, J = 5 Hz, 3 Hz, 1H), 7.39–
7.36 (m, 3H), 7.36–7.33 (m, 2H), 4.11 (d, J = 1.5 Hz, 1H), 4.06 (d,
Yield: 56%; ½a 2D2
ꢁ
¼ ꢀ142:1 (c 1, CH2Cl2) 60% ee; mp 78–80 °C; 1H
NMR (CDCl3, 500 MHz), d (ppm): 8.00 (dd, J = 3.5 Hz, 1 Hz, 1H),
7.76 (dd, J = 5 Hz, 1 Hz, 1H), 7.34 (s, 1H), 7.34–7.30 (m, 1H), 7.31
(d, J = 8 Hz, 1H), 7.25–7.23 (m, 1H), 7.19 (t, J = 4.5 Hz, 1H), 4.15
(d, J = 1.5 Hz, 1H), 4.04 (d, J = 1.5 Hz, 1H). HRMS calcd for
J = 1.5 Hz, 1H). HRMS calcd for
C13H10O2S 230.0402, found
230.0399.
C
13H9ClO2S 264.0012, found 264.0007.
4.2.17. trans-(ꢀ)-2,3-Epoxy-1-(3-thienyl)-3-(2-tolyl)-propan-1-
one 9b
4.2.10. trans-(ꢀ)-2,3-Epoxy-1-(2-thienyl)-3-(4-chlorophenyl)-
Yield: 51%; ½a 2D2
ꢁ
¼ ꢀ19:3 (c 1, CH2Cl2) 52% ee; mp 72–74 °C; 1H
propan-1-one 7d
NMR (CDCl3, 500 MHz), d (ppm): 8.39 (dd, J = 2.5 Hz, 1 Hz, 1H),
7.67 (dd, J = 5 Hz, 1 Hz, 1H), 7.37 (dd, J = 5 Hz, 3 Hz, 1H), 7.30 (dd,
J = 8 Hz, 2.5 Hz, 1H), 7.23–7.26 (m, 2H), 7.16–7.19 (m, 1H), 4.24
(d, J = 1.5 Hz, 1H), 3.96 (d, J = 1.5 Hz, 1H), 2.35 (s, 3H). HRMS calcd
for C14H12O2S 244.0558, found 244.0562.
Yield: 54%; ½a 2D2
ꢁ
¼ ꢀ139 (c 1, CH2Cl2) 65% ee; mp 80–82 °C; 1H
NMR (CDCl3, 500 MHz), d (ppm): 8.00 (d, J = 3.5 Hz, 1H), 7.75 (d,
J = 5 Hz, 1H), 7.37 (d, J = 8 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 7.18 (t,
J = 4.5 Hz, 1H), 4.15 (d, J = 1.5 Hz, 1H), 4.02 (d, J = 1.5 Hz, 1H). HRMS
calcd for C13H9ClO2S 264.0012, found 264.0014.
4.2.18. trans-(ꢀ)-2,3-Epoxy-1-(3-thienyl)-3-(1-naphthyl)-prop-
4.2.11. trans-(ꢀ)-2,3-Epoxy-1-(2-thienyl)-3-(4-fluorophenyl)-
an-1-one 9c
propan-1-one 7e
Yield: 66%; ½a 2D2
ꢁ
¼ þ51:9 (c 1, CH2Cl2) 54% ee; Oil. 1H NMR
Yield: 55%; ½a 2D2
ꢁ
¼ ꢀ119:7 (c 1, CH2Cl2) 62% ee; mp 64–66 °C; 1H
(CDCl3, 500 MHz), d (ppm): 8.40 (dd, J = 3 Hz, 1 Hz, 1H), 8.00–
7.97 (m, 1H), 7.93–7.89 (m, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.72 (dd,
J = 5 Hz, 1 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.54–7.51 (m, 2H), 7.49
(d, J = 7.5 Hz, 1H), 7.38 (dd, J = 5 Hz, 3 Hz, 1H), 4.74 (d, J = 1.5 Hz,
NMR (CDCl3, 500 MHz), d (ppm): 8.01 (d, J = 3.5 Hz, 1H), 7.75 (d,
J = 4.5 Hz, 1H), 7.33 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 5.5 Hz, 1H),
7.18 (t, J = 4.5 Hz, 1H), 7.09 (d, J = 3.5 Hz, 1H), 7.07 (d, J = 3.5 Hz,

1194
Z. Rapi et al. / Tetrahedron: Asymmetry 22 (2011) 1189–1196
1H), 4.09 (d, J = 1.5 Hz, 1H). HRMS calcd for C17H12O2S 280.0558,
found 280.0553.
4.3.3. 1-(2-N-Methylpyrrolyl)-3-(3-chlorophenyl)-propen-2-en-
1-one 15c
Yield: 45%; mp 87–88 °C; 1H NMR (CDCl3, 300 MHz) d (ppm):
7.66 (d, J = 15.6 Hz, 1H), 7.59 (s, 1H), 7.48–7.44 (m, 1H), 7.38 (d,
J = 15.6 Hz, 1H), 7.35–7.32 (m, 2H), 7.11 (dd, J = 4.2 Hz, 1.5 Hz,
1H), 6.89 (m, 1H), 6.21 (dd, J = 3.9 Hz, 2.4 Hz, 1H), 4.03 (s, 3H).
4.2.19. trans-(ꢀ)-2,3-Epoxy-1-(2-pyrrolyl)-3-phenylpropan-1-
one 12a
Yield: 33%; ½a 2D2
ꢁ
¼ ꢀ77:3 (c 1, CHCl3) 36% ee; mp 139–140 °C;1H
NMR (CDCl3, 300 MHz) d (ppm): 9.69 (br s, 1H), 7.41–7.31 (m, 5H),
7.18 (m, 1H), 7.14 (m, 1H), 6.34 (m, 1H), 4.17 (d, J = 1.5 Hz, 1H),
4.01 (d, J = 1.5 Hz, 1H). HRMS calcd for C13H11NO2 213.0790, found
213.0785.
4.3.4. 1-(2-N-Methylpyrrolyl)-3-(4-chlorophenyl)-propen-2-en-
1-one 15d
Yield: 52%; mp 122–124 °C; 1H NMR (CDCl3, 500 MHz) d
(ppm):7.67 (d, J = 15.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2 H), 7.37 (d,
J = 8.5 Hz, 2H), 7.36 (d, J = 15.5 Hz, 1 H), 7.10 (d, J = 3 Hz, 1H),
6.89 (m, 1H), 6.20 (dd, J = 3.5 Hz, 2.5 Hz, 1H), 4.03 (s, 3H).
4.2.20. trans-(ꢀ)-2,3-Epoxy-1-(2-pyrrolyl)-3-(2-tolyl)-propan-1-
one 12b
Yield: 28%; ½a 2D2
ꢁ
¼ ꢀ1:2 (c 1, CHCl3) 20% ee; mp 125–127 °C; 1H
NMR (CDCl3, 300 MHz) d (ppm): 9.88 (br s, 1H), 7.33–7.29 (m, 1H),
7.26–7.22 (m, 2H), 7.19 (m, 2H), 7.16 (m, 1H), 6.34 (m, 1H), 4.30 (d,
J = 1.5 Hz, 1H), 3.92 (d, J = 1.5 Hz, 1H), 2.36 (s, 3H). HRMS calcd for
4.3.5. 1-(2-N-Methylpyrrolyl)-3-(2-tolyl)-propen-2-en-1-one
15e
Yield: 55%; mp 90–91 °C; 1H NMR (CDCl3, 500 MHz) d (ppm):
8.03 (d, J = 15.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.32 (d,
J = 15.5 Hz, 1H), 7.28–7.20 (m, 3H), 7.11 (dd, J = 4.2 Hz, 1.5 Hz,
1H), 6.88 (m, 1H), 6.20 (dd, J = 4.1 Hz, 2.4 Hz, 1H), 4.04 (s, 3H),
2.47 (s, 3H).
C14H13NO2 227.0946, found 227.0950.
4.2.21. (2R,3S)-2,3-Epoxy-1-(2-pyrrolyl)-3-(1-naphthyl)-propan-
1-one 12c
Yield: 22%; ½a 2D2
ꢁ
¼ þ24:9 (c 1, CHCl3) 51% ee; After repeated
¼ þ56:5 (c 1, CHCl3) 100% ee; mp 168 °C (de-
crystallizations: ½a D22
ꢁ
4.3.6. 1-(2-N-Methylpyrrolyl)-3-(3-tolyl)-propen-2-en-1-one 15f
Yield: 37%; mp 59–60 °C; 1H NMR (CDCl3, 500 MHz) d (ppm):
7.71 (d, J = 15.5 Hz, 1H), 7.42 (s, 1H), 4.41 (d, J = 4.5 Hz, 1H), 7.39
(d, J = 15.5 Hz, 1H), 7.29 (t, J = 3 Hz, 1H), 7.19 (d, J = 4.5 Hz, 1H),
7.12 (dd, J = 4.2 Hz, 1.5 Hz, 1H), 6.87 (m, 1H), 6.20 (dd, J = 3.5 Hz,
2.5 Hz, 1H), 4.03 (s, 3H), 2.39 (s, 3H).
compd.); 1H NMR (CDCl3, 500 MHz) d (ppm): 9.67 (br s, 1H), 8.02–
7.99 (m, 1H), 7.91–7.90 (m, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.58 (d,
J = 7 Hz, 1H), 7.54–7.50 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.20–7.16
(m, 2H), 6.35 (dd, J = 5 Hz, 2.5 Hz, 1H), 4.79 (d, J = 1.5 Hz, 1H),
4.04 (d, J = 1.5 Hz, 1H). HRMS calcd for C18H13NO2 263.0946, found
263.0944.
4.3.7. 1-(2-N-Methylpyrrolyl)-3-(4-tolyl)-propen-2-en-1-one
15g
4.2.22. trans-(ꢀ)-2,3-Epoxy-1-(2-pyrrolyl)-3-(2-naphthyl)-prop-
an-1-one 12d
Yield: 41%; mp 65–66 °C; 1H NMR (CDCl3, 500 MHz) d (ppm):
7.72 (d, J = 15.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 2H), 7.36 (d,
J = 15.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 2H), 7.11 (dd, J = 4.2 Hz,
1.5 Hz, 1H), 6.87 (m, 1H), 6.20 (dd, J = 3.5 Hz, 2.5 Hz, 1H), 4.03 (s,
3H), 2.38 (s, 3H).
Yield: 29%; ½a 2D2
ꢁ
¼ ꢀ40 (c 1, CHCl3) 18% ee; mp 138–141 °C; 1H
NMR (CDCl3, 500 MHz) d (ppm): 9.65 (br s, 1H), 7.83–7.88 (m, 4H),
7.49–7.53 (m, 2H), 7.39 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.19 (m, 1H),
7.14 (m, 1H), 6.33–6.35 (m, 1H), 4.34 (d, J = 1.5 Hz, 1H), 4.11 (d,
J = 1.5 Hz, 1H). HRMS calcd for
C18H13NO2 263.0946, found
263.0949.
4.3.8. 1-(2-N-Methylpyrrolyl)-3-(1-naphthyl)-propen-2-en-1-
one 15h
4.3. General procedure for the preparation of
an N-methylpyrrole unit (15)
a
,b-enones having
This product was extracted with CHCl3 from the mixture after
removal of the solvent, then column chromatographed on silica
gel (eluent hexane/ethyl-acetate 100:5).
To a stirred solution of 2-acetyl-N-methylpyrrole (10 mmol)
and the appropriate aromatic aldehyde (10 mmol) in 96% ethanol
(8 cm3), 10% aqueous KOH (8 cm3) was added and stirred at rt.
After the reaction was completed (monitored by TLC), the precipi-
tate was filtered, washed with 96% ethanol and water, then dried.
In case there was no precipitation, the solvent was removed from
the mixture and the solid phase was filtered, then washed with
96% ethanol, with water, and finally dried. The crude product
was crystallized from 96% ethanol (These procedures were not
optimized).
Yield: 63%; Oil. 1H NMR (CDCl3, 300 MHz) d (ppm): 8.58 (d,
J = 15.3 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.90–7.86 (m, 2H), 7.85
(d, J = 7.2 Hz, 1H), 7.59–7.52 (m, 2H), 7.49 (d, J = 8.1 Hz, 1H) 7.47
(d, J = 15.3 Hz, 1H), 7.15 (dd, J2 = 4.2 Hz, 1.5 Hz, 1H), 6.90 (m, 1H),
6.21 (dd, J = 4.1 Hz, 2.4 Hz, 1H), 4.07 (s, 3H).
4.3.9. 1-(2-N-Methylpyrrolyl)-3-(2-naphthyl)-propen-2-en-1-
one 15i
Yield: 42%; mp 126–128 °C; 1H NMR (CDCl3, 500 MHz) d (ppm):
8.00 (s, 1H), 7.89 (d, J = 15.5 Hz, 1H), 7.89–7.82 (m, 3H), 7.77 (d,
J = 8.5 Hz, 1H), 7.53 (d, J = 15.5 Hz, 1H), 7.52–7.49 (m, 2H), 7.17
(dd, J = 4.2 Hz, 1.5 Hz, 1H), 6.89 (m, 1H), 6.22 (dd, J = 3.5 Hz,
2.5 Hz, 1H), 4.05 (s, 3H).
4.3.1. 1-(2-N-Methylpyrrolyl)-3-phenylpropen-2-en-1-one 15a
Yield: 86%; mp 108–110 °C; 1H NMR (CDCl3, 500 MHz) d (ppm):
7.73 (d, J = 15.5 Hz, 1H), 7.61 (d, J = 7 Hz, 2H), 7.42 (m, 1H), 7.39 (m,
2H), 7.38 (d, J = 15.5 Hz, 1H), 7.11 (d, J = 3 Hz, 1H), 6.88 (m, 1H),
6.20 (dd, J = 3.5 Hz, 2.5 Hz, 1H), 4.04 (s, 3H).
4.4. General procedure for the epoxidation of a,b-enones 15a–i
with a 2-N-methylpyrrole unit
4.3.2. 1-(2-N-Methylpyrrolyl)-3-(2-chlorophenyl)-propen-2-en-
1-one 15b
To a solution of a,b-enone (1.44 mmol) and the appropriate cat-
alyst (0.1 mmol) in toluene (3 mL) was added 20% aq NaOH (1 mL)
and the mixture was treated with 0.5 mL 5.5 M tert-butyl hydro-
peroxide in decane (2.88 mmol). The mixture was stirred at rt for
46–240 h. A new portion of toluene (7 mL) and water (2 mL) was
then added and the mixture was stirred for several minutes. The
organic phase was washed with 10% aqueous hydrochloric acid
Yield: 62%; mp 82–84 °C; 1H NMR (CDCl3, 300 MHz) d (ppm):
8.13 (d, J = 15.6 Hz, 1H), 7.71 (dd, J = 5.7 Hz, 3.6 Hz, 1H), 7.42 (dd,
J = 5.7 Hz, 3.6 Hz, 1H), 7.37 (d, J = 15.6 Hz, 1H), 7.29 (dd,
J = 5.7 Hz, 3.6 Hz, 2H), 7.10 (dd, J = 4.2 Hz, 1.5 Hz, 1H), 6.89 (m,
1H), 6.20 (dd, J = 4.1 Hz, 2.4 Hz, 1H), 4.04 (s, 3H).

Z. Rapi et al. / Tetrahedron: Asymmetry 22 (2011) 1189–1196
1195
(2 ꢂ 10 mL) and then with water (10 mL). The organic phase was
dried (Na2CO3). The crude product obtained after evaporating the
solvent was purified by preparative TLC (silica gel, hexane–ethyl
acetate, 10:1 as the eluant) to give the chiral epoxyketone in a pure
form. The enantiomeric excess was determined by 1H NMR spec-
troscopy in the presence of Eu(hfc)3 as a chiral shift reagent.
J = 1.8 Hz, 1H), 3.99 (s, 3H), 2.36 (s, 3H). HRMS calcd for
15H15NO2 241.1103, found 241.1107.
C
4.4.8. trans-(+)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-(1-naphthyl)-
propan-1-one 13h
Yield: 72%; Oil. ½a D22
ꢁ
¼ þ88 (c 1, CHCl3) 70% ee; 1H NMR (CDCl3,
300 MHz) d (ppm): 8.04–8.01 (m, 1H), 7.92–7.89 (m, 1H), 7.84 (d,
J = 8.4 Hz, 1H), 7.59 (d , J = 6.9 Hz, 1H), 7.55–7.50 (m, 2H), 7.48
(d, J = 9 Hz, 1H), 7.14 (dd, J = 3.9 Hz, 1.5 Hz, 1H), 6.94 (m, 1H),
6.17 (dd, J = 3.9 Hz, 2.4 Hz, 1H), 4.75 (d, J = 1.8 Hz, 1H), 4.09 (d,
J = 1.8 Hz, 1H), 4.06 (s, 3H). HRMS calcd for C18H15NO2 277.1103,
found 277.1106.
4.4.1. trans-(ꢀ)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-phenylprop-
an-1-one 13a
Yield: 80%; Oil. ½a D22
ꢁ
¼ ꢀ209:5 (c 1, CHCl3) 79% ee; 1H NMR
(CDCl3, 500 MHz) d (ppm):7.39–7.34 (m, 5H), 7.14 (dd, J = 4 Hz,
1.5 Hz, 1H), 6.91 (m, 1H), 6.17 (dd, J = 4 Hz, 2.5 Hz, 1H), 4.11 (d,
J = 1.5 Hz, 1H), 4.06 (d, J = 1.5 Hz, 1H), 3.99 (s, 3H). HRMS calcd
for C14H13NO2 227.0946, found 227.0941.
4.4.9. trans-(ꢀ)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-(2-naphthyl)-
propan-1-one 13i
Yield: 69%; ½a 2D2
ꢁ
¼ ꢀ219:7 (c 1, CHCl3) 77% ee; mp 92–96 °C; 1H
4.4.2. trans-(ꢀ)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-(2-chloro-
phenyl)-propan-1-one 13b
NMR (CDCl3, 300 MHz) d (ppm): 7.88–7.82 (m, 4H), 7.52–7.48 (m,
2H), 7.40 (dd, J = 8.7 Hz, 1.2 Hz, 1H), 7.15 (dd, J = 4.2 Hz, 1.2 Hz,
1H), 6.92 (m, 1H), 6.17 (dd, J = 3.9 Hz, 2.4 Hz, 1H), 4.28 (d,
J = 1.5 Hz, 1H), 4.16 (d, J = 1.5 Hz, 1H), 4.01 (s, 3H). HRMS calcd
for C18H15NO2 277.1103, found 277.1100.
Yield: 73%; ½a 2D2
ꢁ
¼ ꢀ7 (c 1, CHCl3) 51% ee; mp 61–64 °C; 1H
NMR (CDCl3, 500 MHz) d (ppm): 7.38 (t, J = 2.5 Hz, 1H), 7.36 (t,
J = 2.5 Hz, 1H), 7.30–7.28 (m, 2H), 7.16 (dd, J = 4.5 Hz, 1.5 Hz, 1H),
6.93 (m, 1H), 6.18 (dd, J = 4 Hz, 2.5 Hz, 1H), 4.44 (d, J = 2 Hz, 1H),
4.01 (s, 3H), 3.95 (d, J = 2 Hz, 1H). HRMS calcd for C14H12ClNO2
261.0557, found 261.0560.
Acknowledgments
4.4.3. trans-(ꢀ)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-(3-chloro-
Financial support by the Hungarian Scientific Research Fund
(OTKA No. K 75098 and K 81127) is gratefully acknowledged. This
work is connected to the scientific program of the Development
of quality-oriented and harmonized R+D+I strategy and functional
model at BME project. This project is supported by the New
Hungary Development Plan (Project ID:TÁMOP-4.2.1/B-09/1/
KMR-2010-0002). One of us (R.Z.) is grateful for the Gedeon
Richter Plc fellowship.
phenyl)-propan-1-one 13c
Yield: 88%; ½a 2D2
ꢁ
¼ ꢀ207 (c 1, CHCl3) 79% ee; mp 81–83 °C; 1H
NMR (CDCl3, 500 MHz) d (ppm): 7.33 (s, 1H), 7.32 (m, 2H), 7.25–
7.23 (m, 1H), 7.14 (dd, J = 3.8 Hz, 1.5 Hz, 1H), 6.93 (m, 1H), 6.18
(dd, J = 4 Hz, 2.5 Hz, 1H), 4.10 (d, J = 2 Hz, 1H), 4.02 (J = 2 Hz, 1H),
3.99 (s, 3H). HRMS calcd for
261.0563.
C14H12ClNO2 261.0557, found
4.4.4. trans-(ꢀ)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-(4-chloro-
References
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Yield: 92%; ½a 2D2
ꢁ
¼ ꢀ211:4 (c 1, CHCl3) 81% ee; mp 89–90 °C; 1H
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Yield: 83%; Oil. ½a D22
ꢁ
¼ ꢀ49:7 (c 1, CHCl3) 65% ee; 1H NMR
(CDCl3, 300 MHz) d (ppm): 7.33–7.30 (m, 1H), 7.26–7.22 (m, 2H),
7.18–7.17 (m, 1H), 7.16 (dd, J = 3.8 Hz, 1.5 Hz, 1H), 6.93 (m, 1H),
6.18 (dd, J = 4 Hz, 2.5 Hz, 1H), 4.25 (d, J = 1.8 Hz, 1H), 4.01 (s, 3H),
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4.4.6. trans-(ꢀ)-2,3-Epoxy-1-(2-N-methylpyrrolyl)-3-(3-tolyl)-
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ꢁ
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}
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ꢁ
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1196
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