Catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and amides by lanthanide-BINOL complexes

Article abstract of DOI:10.1016/j.tet.2003.06.010

Highly enantioselective catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and simple amides was developed. In the presence of 5-10mol% of lanthanide-BINOL complexes, the reaction proceeded smoothly with high substrate generality. In particular, in the cases of α,β-unsaturated amides, there was nearly perfect enantioselectivity (>99% ee). The corresponding epoxides were successfully transformed into many types of useful chiral compounds such as α,β-epoxy esters, α,β-epoxy amides, α,β-epoxy aldehydes, α,β-epoxy β-keto ester, and α- and β-hydroxy carbonyl compounds. B3LYP density functional studies were performed to predict substrate reactivity.

Full text of DOI:10.1016/j.tet.2003.06.010

Tetrahedron 59 (2003) 10485–10497
Catalytic asymmetric epoxidation of a,b-unsaturated carboxylic
acid imidazolides and amides by lanthanide–BINOL complexes
Takashi Ohshima, Tetsuhiro Nemoto, Shin-ya Tosaki, Hiroyuki Kakei, Vijay Gnanadesikan
*
and Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 2 May 2003; accepted 4 June 2003
Abstract—Highly enantioselective catalytic asymmetric epoxidation of a,b-unsaturated carboxylic acid imidazolides and simple amides
was developed. In the presence of 5–10 mol% of lanthanide–BINOL complexes, the reaction proceeded smoothly with high substrate
generality. In particular, in the cases of a,b-unsaturated amides, there was nearly perfect enantioselectivity (.99% ee). The corresponding
epoxides were successfully transformed into many types of useful chiral compounds such as a,b-epoxy esters, a,b-epoxy amides, a,b-epoxy
aldehydes, a,b-epoxy b-keto ester, and a- and b-hydroxy carbonyl compounds. B3LYP density functional studies were performed to predict
substrate reactivity.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
and g,d-epoxy b-keto esters.9 We later succeeded in
catalytic asymmetric epoxidation of simple a,b-unsaturated
amide for the first time.10 This report details our full
investigation of lanthanide–BINOL complex-catalyzed
asymmetric epoxidation of a,b-unsaturated carboxylic
acid derivatives.
Asymmetric epoxidation of a,b-unsaturated carbonyl
compounds has attracted a great deal of attention from
synthetic organic chemists1 because it constructs two
adjacent chiral carbon centers simultaneously and the
corresponding enantiomerically-enriched epoxy compounds
can be easily converted to many types of useful chiral
compounds.2 Since the initial report by Julia and
´
2. Results and discussion
co-workers,3 catalytic asymmetric epoxidation of a,b-un-
saturated ketones (enones) has been studied and several
successful methods have been reported.1,4,5 There are only a
few reports, however, of a,b-unsaturated carboxylic acid
derivatives. A salen-manganese complex6 or an optically-
active ketone7 was used for catalytic asymmetric epoxi-
dation of a,b-unsaturated esters. Substrates that have other
functional groups, such as a C–C double bond or ketone,
cannot be used for those asymmetric reactions due to poor
chemoselectivity. Our strategy relies on the Weitz–Scheffer
type epoxidation8 using 1,4-addition of hydroperoxide as
an initial step, thus chemoselective epoxidation of electron-
deficient alkenes in the presence of other olefins is realized.
We recently reported the first example of catalytic
epoxidation of a,b-unsaturated carboxylic acid imidazo-
lides by the La–BINOL–Ph3AsvO (1:1:1) complex 1 and
efficient transformations of the corresponding epoxidation
products: a,b-epoxy peroxy tert-butyl esters into the
a,b-epoxy esters, a,b-epoxy amides, a,b-epoxy aldehydes,
2.1. Catalytic asymmetric epoxidation of
a,b-unsaturated carboxylic acid imidazolides
We first examined catalytic asymmetric epoxidation of
a,b-unsaturated ester: ethyl (E)-cinnamate (2a). We
previously developed a general and practical catalytic
asymmetric epoxidation of a,b-unsaturated ketones using
the La–BINOL–Ph3AsvO complex 1 generated from
La(O-i-Pr)3, BINOL, and Ph3AsvO in a ratio of 1:1:1.3d
Using 20 mol% of complex 1, the epoxidation of 2a
proceeded to afford a,b-epoxy ester 3a in 90% ee. The
obtained yield, however, was only 5% even after 48 h
(Scheme 1). To enhance substrate reactivity, we examined
Keywords: asymmetric catalysis; epoxidation; lanthanide; molecular orbital
calculation.
*
Corresponding author. Tel.: þ81-3-5684-0651; fax: þ81-3-5684-5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp
Scheme 1. Catalytic asymmetric epoxidation of ethyl (E)-cinnamate (2a).
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.06.010

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T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
We then turned our attention to catalytic asymmetric
epoxidation of activated a,b-unsaturated amides, which
would be expected to enhance the reactivity by decreasing
the lowest unoccupied molecular orbital (LUMO) energy.
N-Acyloxazolidinones are one of the most well-known
activated amides and they are utilized in various catalytic
asymmetric reactions.11 Thus, we first examined a catalytic
asymmetric epoxidation of N-cinnamoyloxazolidinone
(5) using 20 mol% of complex 1. In contrast to the cases
of a,b-unsaturated esters, the reaction proceeded to
completion in 48 h, providing an unexpected product:
a,b-epoxy peroxycarboxylic acid tert-butyl ester 6a with
10–20% of 4a (Scheme 2).
Scheme 2. Catalytic asymmetric epoxidation of N-cinnamoyloxazolidinone
(5).
To further improve reactivity and selectivity, we investi-
gated other activated a,b-unsaturated amides as substrates.
Semiempirical molecular orbital calculation (AM1)12
revealed that the energy of the LUMO of 5 was 0.216 eV
(5.0 kcal/mol) lower than that of 2a. This result prompted us
to perform detailed calculations to find a more reactive
substrate. On the basis of our preliminary AM1 calculations,
N-acylimidazoles (a,b-unsaturated carboxylic acid imidazo-
lide) 7a was predicted to be a more reactive candidate due to
a lower LUMO energy than that of 5. Later, more precise
calculation studies were performed13 by means of the
B3LYP14 hybrid density functional method using a 6-31G(d)
basis set (vide infra). Carboxylic acid imidazolides are
widely used in organic synthesis, mainly as acylation
reagents.15 They have not yet been used, however, in an
Scheme 3. Catalytic asymmetric epoxidation of N-cinnamoylimidazole
(7a).
more reactive a,b-unsaturated esters, such as p-nitrophenyl
ester 2b, pentafluorophenyl ester 2c, and hexafluoroiso-
propyl ester 2d as substrates. In these cases, only trans-
esterification occurred to afford 4a, which remained
unchanged in the reaction medium.
Table 1. Catalytic asymmetric epoxidation of various cinnamates and the results of AM1 and B3LYP calculations
Entry
X
Substrates
LUMO energy (eV)
Time (h)
48
Yield (%)
ee (%)
90
AMI
B3LYP
1
2
3
–OEt
–OC6F5
–OO-t-Bu
2a
2c
4a
20.68
20.86
21.70
22.19
21.82
5
4
5
20.87
22.05
24
73
87
5
6
7a
7b
20.97
20.99
22.34
22.25
4
86
70
91
77
12
7
7c
21.02
22.27
3
85
92
8
9
7d
7e
20.97
21.07
22.34
22.37
12
1
69
91
87
94
10
11
7f
20.96
21.07
22.24
22.41
24
1
80
63
–
10
Trace

T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
10487
asymmetric reaction as a substrate, perhaps because of their
high reactivity at the carbonyl carbon toward nucleophiles.
Despite these negative factors, we assumed that a soft
nucleophile might attack at the b-carbon in preference to the
carbonyl carbon. Thus, we investigated a catalytic asym-
metric epoxidation using 7a as a representative starting
material. The epoxidation of 7a proceeded successfully by
using the La–BINOL–Ph3AsvO complex 1 (20 mol%, rt,
4 h) to afford 8a in 86% yield with 91% ee with 4a (5–10%)
after direct methanolysis (Scheme 3). During the epoxida-
tion, a,b-epoxy carboxylic acid imidazolide 9a was not
detected by thin-layer chromatography and electronspray
ionization-mass analysis. In addition, a,b-unsaturated
peroxy ester 4a was not converted to 6a under the same
conditions. These findings suggest that the epoxidation of 7a
proceeded in preference to transesterification to afford 9a,
which was spontaneously converted to 6a.
91% yield, 94% ee). In this case, only a trace amount of 4a
was obtained. These results indicated that 4-phenylimida-
zolide effectively enhanced the reactivity at the b-carbon
toward the soft nucleophile. Enhancement of the reactivity
appeared to be related to the decrease in LUMO energy with
some exception such as triazolide 10, which afforded the
peroxy ester 4a as a major product.
Having developed an efficient catalytic asymmetric syn-
thesis of 8a from 7e, we examined the scope and limitations
of different substrates. This newly-developed system had
broad generality for epoxidations of various a,b-unsatu-
rated carboxylic acid 4-phenylimidazolides to afford the
corresponding epoxides 8a, 8g–p (Table 2). When 10 mol%
of complex 1 and 2.4 equiv. of tert-butyl hydroperoxide
(TBHP) were used at room temperature, all epoxidations of
b-aryl type substrates proceeded to completion with
reasonable reaction times (3.5–6 h). In the case of 7e,
even 5 mol% of 1 promoted the reaction efficiently to
give 8a (yield 73%, 85% ee, entry 2). Other b-aryl type
substrates, which have an electron-withdrawing group
(entries 5, 6) or an electron donating group (entry 7) on
the aromatic ring, were smoothly epoxidized to afford 8g,h,
or 8i in good enantiomeric excess (89–93% ee). This
asymmetric catalyst system was also effective for b-alkyl
substituted type substrates with higher reactivity than the
b-aryl type substrates (entries 8–16). Both primary (entries
8–15) and secondary (entry 16) alkyl substituted substrates
gave the products in high yield (72–93%) and slightly lower
enantiomeric excess (79–88% ee). Particularly noteworthy
is that this reaction was applicable to substrates that were
functionalized with a C–C double bond (entries 12–14) or a
ketone (entry 15), without overoxidation. To the best of our
knowledge, this is the first example of a general catalytic
asymmetric epoxidation of a,b-unsaturated carboxylic acid
derivatives.
We then investigated the effects of amide moieties in
the reaction, which are summarized in Table 1 with the
results of AM1 and B3LYP calculations. Among them,
4-phenylimidazolide 7e, which has a lower LUMO energy
than other imidazolides, gave the best result in terms of
reactivity, chemical yield, and enantiomeric excess (1 h,
Table 2. Catalytic asymmetric epoxidation of various a,b-unsaturated
carboxylic acid 4-phenylimidazolides using 10 mol% of 1
Entry
R
Substrate Product Time Yield
(%)
ee
(%)
(h)
1
Ph–
7e
7e
7e
7e
7g
7h
7i
8a
8a
8a
8a
8g
8h
8i
3.5
12
3.5
18
5
86
73
85
47
91
86
80
92
85
94
94
93
89
91
2a
3b
4c
5
The addition of 3–6 equiv. of Ph3PvO to the lanthanide–
BINOL complex also enhances the rate of this reaction. In
fact, catalytic asymmetric epoxidation of 7e and 7j using the
4-Cl–C6H4–
4-Br–C6H4–
4-MeO–C6H4–
6d
7
4
6
Table 3. The central metal effects for the epoxidation of 7j and 7k
8
7j
8j
1
86
83
9b
10c
7j
7j
8j
8j
1
11
84
58
87
91
11
12
13
14
7k
8k
1
93
93e
92e
85
79
86
79
82
7l
8l
2
Entry
R
Ln
Time (h)
Yield (%)
ee (%)
7m
7n
8m
8n
1.5
2
1
Ph(CH2)22(7j)
La (1)
Pr (12)
Pr (13)
Sm
Gd
Dy
1
1.5
4
6
3
3
20
1
1.5
7
5
86
87
82
81
81
79
78
93
88
92
88
84
85
71
83
85
86
79
67
77
68
79
86
88
65
49
76
56
2
3a
4
5
6
7
8
15
7o
7p
8o
8p
4
4
81e
72e
81
88
Yb
Ph(CH2)42(7k)
La (1)
Pr (12)
Pr (13)
Sm
Gd
Dy
16
9
10a
11
12
13
14
a
5 mol% of the catalyst was used.
30 mol% of Ph3PvO was used instead of 10 mol% of Ph3AsvO.
Cumene hydroperoxide was used as an oxidant.
4-Methylimidazolide was used due to the low solubility of the
corresponding 4-phenylimidazolide.
Isolated yield of the corresponding peroxycarboxylic acid tert-butyl ester.
b
c
d
8
2
18
Yb
e
a
30 mol% of Ph3PvO was used instead of 10 mol% of Ph3AsvO.

10488
T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
La–BINOL–Ph3PvO5 (1:1:3) complex 11 afforded similar
results (entries 3, 9). In addition, we examined reactions
using cumene hydroperoxide (CMHP) as an oxidant. As
shown in entries 4 and 10, the corresponding epoxy esters
were obtained with higher selectivity compared to those
obtained using TBHP. There was, however, a remarkable
decrease in reactivity.
Scheme 5.
As mentioned above, the b-alkyl substituted type substrates
had slightly lower enantioselectivity. To further improve
selectivity, the effects of the central metal for the
epoxidations of 7j and 7k were investigated using
10 mol% of Ln–BINOL–Ph3AsvO complex, generated
from Ln(O-i-Pr)3, BINOL, and Ph3AsvO in a ratio of 1:1:1.
The results are summarized in Table 3. The Pr–BINOL–
Ph3AsvO (1:1:1) complex 12 was the best catalyst for
both substrates, affording the highest enantioselectivity. The
Pr–BINOL–Ph3PvO (1:1:3) complex 13 was also an
effective catalyst with lower reactivity and slightly higher
selectivity than 12 (entries 3, 10). In the case of the b-aryl
type substrates, the original catalyst La–BINOL–Ph3AsvO
(1:1:1) complex 1 gave the best results.
they were converted to the corresponding a,b-epoxy amides
14 (93%) and 17 (98%), the g,d-epoxy b-keto esters 15
(77%) and 18 (85%), and the a,b-epoxy aldehydes 16 (70%)
and 19 (71%) by the addition of amine, lithium ester
enolate, and aluminum hydrides (Red-Al or DIBAH),
respectively, without any epoxide ring opening reactions.9
In addition, the epoxide product 8i is a key intermediate
for one of the most potent calcium antagonists diltiazem
(Herbesser)16 (Scheme 5). Further transformation using a
tandem process will be discussed in the last section.
2.2. Catalytic asymmetric epoxidation of a,b-
unsaturated simple amides
Chiral a,b-epoxy amides are very important compounds
because they can be converted into useful chiral building
blocks such as a- and b-hydroxy amides. As demonstrated
in Scheme 4, many chiral a,b-epoxy amides can be
synthesized from the corresponding a,b-epoxy peroxy
esters. Catalytic asymmetric epoxidation of a,b-unsaturated
amides should be a more direct and efficient method for the
preparation of chiral a,b-epoxy amides. There are no
reports, however, of catalytic asymmetric epoxidation of
a,b-unsaturated amides,17 perhaps due to the lower
reactivity (LUMO energy of N-methyl cinnamoyl amide
(20k): 21.46 eV) than that of a,b-unsaturated ester
(21.70 eV, Table 1, entry 1). While catalytic asymmetric
epoxidation of a,b-unsaturated esters proceeded very
sluggishly with the use of complex 1, surprisingly,
a,b-unsaturated amides were epoxidized more smoothly
under the same conditions. This result prompted us to
The usefulness of the intermediates 6a (b-aryl type) and
6j (b-alkyl type) was demonstrated (Scheme 4). The
a,b-epoxy peroxy esters 6a and 6j are stable compounds,
which were isolated using common flash column chroma-
tography and can be stored at least 2 months in a refrigerator
(at 48C). On the other hand, they are so-called active-esters,
thus many kinds of nucleophiles can react very smoothly at
the carbonyl carbon in preference to the epoxide. In fact,
Table 4. Effect of the amount of TBHP and the central metal for the
epoxidation of 20a
Entry
Ln
TBHP (equiv.)
1.1
1.2
1.5
2.0
2.4
1.2
1.2
Time (h) Yield (%) ee (%)
1
2
3
4
La (1)
La (1)
La (1)
La (1)
La (1)
Pr (12)
Pr (13)
48
48
48
48
48
8
29
93
63
57
40
96
48
97
65
71
94
25
91
97
98
97
94
99.1
95
5
6
7a
8
24
8
24
24
8
Sm (22) 1.2 (condition A)
Sm (23) 1.2
Gd
Dy
Yb
99.4
96
94
98
9a
10
11
12
1.2
1.2
1.2
Scheme 4. Further transformations of a,b-epoxy peroxy esters 6a and
6j. Conditions: (a) methylamine (2.5 equiv.), THF, 08C; (b) ethyl
acetate (2.5 equiv.), LiHMDS (2.0 equiv.), THF, 2788C; (c) Red-Al
(0.5 mol equiv.), toluene, 2788C; (d) DIBAL (1.0 equiv.), toluene, 2788C.
24
65
a
30 mol% of Ph3PvO was used instead of 10 mol% of Ph3AsvO.

T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
10489
Table 5. Effect of MS 4A for the epoxidation of 20k
also effective, however, in the case of epoxidation of
a,b-unsaturated simple amides, Ph3AsvO always gave
better results (Table 4, entries 7, 9; Table 5, entry 5).
The scope and limitations using numerous substrates were
examined. As shown in Table 6, this catalytic system had a
broad generality for epoxidations of various b-alkyl and
b-aryl type amides. When 5–10 mol% of 22 was used
(condition A), b-alkyl type amides 20a–j, prepared from
primary amines (entries 1–5, 10–12), a-branched primary
amines (entries 6, 7), and secondary amines (entries 8, 9),
were smoothly epoxidized to afford the corresponding
a,b-epoxy amides in excellent yield and in excellent
enantiomeric excess. The scope and limitations of several
b-aryl type amides were also examined using condition B
and all cases afforded satisfactory results (entries 13–17).
To the best of our knowledge, this is the first example of
a general catalytic asymmetric epoxidation of a,b-unsatu-
rated amides.
Entry
MS 4A
Additive
Time (h)
Yield (%)
ee (%)
1a
2
not dried
driedb
–(condition A)
H2Oc
–(condition B)
–
24
18
18
9
89
80
95
92
99.6
99.2
98.8
97.1
3
driedb
4d
driedb
a
Decane solution of TBHP (not dried) was used.
MS 4A was dried for 3 h at 1808C under reduced pressure.
4 equiv. of H2O to the catalyst was added.
30 mol% of Ph3PvO was used instead of 10 mol% of Ph3AsvO.
b
c
d
optimize the reaction conditions. The effect of the central
metal and the amount of TBHP were investigated in detail
using 20a as a representative substrate. The amount of
TBHP strongly affected reactivity and 1.2 equiv. of TBHP
to 20a was optimal (Table 4, entry 2). Sm–BINOL–
Ph3AsvO complex 22, generated from Sm(O-i-Pr)3,
(S)-BINOL, and Ph3AsvO in a ratio of 1:1:1, was the
best catalyst for this reaction (Table 4, entry 8: condition A).
The nearly optically-pure a,b-epoxy amides obtained were
successfully transformed into several useful a- and
b-hydroxy carbonyl compounds. Optically-active b-aryl
a-hydroxy amides are biologically important structural
units and can be easily synthesized from b-aryl a,b-epoxy
amides. To achieve efficient transformation, we developed a
one-pot tandem catalytic asymmetric epoxidation-Pd-cata-
lyzed epoxide opening process.10a,18 A representative result
is shown in Scheme 6. After completion of the epoxida-
tion,19 both 5 mol% of Pd–C and MeOH were directly
added to the reaction mixture and the mixture was stirred
under hydrogen atmosphere. The sequential process func-
tioned efficiently, affording the corresponding a-hydroxy
amide 24 in excellent overall yield and enantiomeric excess.
In the process, beneficial modifications of the Pd catalyst
were achieved by the constituents of the first epoxidation,
This condition was also effective for the epoxidation of
b-aryl type amides with lower reactivity. To enhance
reactivity, further optimization of the reaction was
performed. After investigation of the amount of TBHP
and the central metal, condition A (Sm–BINOL–Ph3AsvO
complex 22 and 1.2 equiv. of TBHP to 20k) also gave the
best result. In these cases, activation of MS 4A was
necessary to improve the lower reactivity, but there was a
slight decrease in enantiomeric excess (Table 5, entry 4:
condition B). Sm–BINOL–Ph3PvO complex 23 was
Table 6. Catalytic asymmetric epoxidation of various a,b-unsaturated amides
Entry
Substrate
Conditions
Time (h)
Yield (%)
ee (%)
R1
NR2R3
CH3NH
1
Ph(CH2)2
Ph(CH2)2
20a
20a
20b
20b
20c
20d
20e
20f
A
A
A
A
A
A
A
A
A
8
24
6
24
4
11
22
3
99
94
97
82
95
97
91
96
94
.99
.99
.99
99
98
.99
99
2a
3
BnNH
4a
5
6
7
8
9
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
AllylNH
cyclo-HexNH
t-BuNH
(CH3)2N
99
.99
20g
4
10
11
12
13
14
15
16
17
Ph(CH2)4
C3H7
cyclo-Hex
Ph
Ph
Ph
4-F–C6H4
4-Me–C6H4
CH3NH
BnNH
BnNH
CH3NH
BnNH
(CH3)2N
CH3NH
CH3NH
20h
20i
20j
20k
20l
20m
20n
20o
A
A
A
B
B
B
B
B
8
9
81
94
90
95
91
96
94
89
.99
94
.99
99
.99
.99
99
12
18
18
9
20
21
.99
a
5 mol% of the catalyst 22 was used.

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T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
Scheme 6. One-pot tandem catalytic asymmetric epoxidation—Pd-catalyzed epoxide opening process.
producing a more suitable catalyst for the second epoxide
opening reaction.20 This one-pot tandem process was also
applied to the syntheses of b-aryl-lactyl-Leu sequences,21
which can be utilized for the synthesis of a neuropeptide
Antho-RNamide (L-3-phenylactyl-Leu-Arg-Asn-NH2),21a
using a,b-unsaturated carboxylic acid imidazolide as a
starting material. In addition, a,b-epoxy amide was
effectively converted to both syn- and anti-3,5-dihydroxy
ester units, which were used for the enantioselective total
syntheses of 1,3-polyol/a-pyrone natural products.10b
lanthanide metal to the b-carbon of an a,b-unsaturated
carbonyl compound, which also coordinated to the lantha-
nide metal in a syn-s-cis manner. Catalytic asymmetric
epoxidation of N-cinnamoyloxazolidinone (5) and a,b-un-
saturated Weinreb amide 26 gave unsatisfactory results,
which can be explained by the unfavorable anti coordination
(Scheme 7).
Although a,b-unsaturated amide was assumed to have
lower reactivity than a,b-unsaturated ester based on the
molecular orbital calculations, epoxidation of a,b-unsatu-
rated amide proceeded much more effectively (99% yield,
.99% ee) than that of a,b-unsaturated ester (16% yield,
85% ee) (Scheme 8).
2.3. Mechanistic investigations
Based on X-ray analysis, laser desorption/ionization time-
of-flight mass spectrometry, kinetic studies, and asymmetric
amplification studies,4d asymmetric epoxidation proceeded
through internal delivery of tert-butyl peroxide from
In the latter case, the reaction proceeded smoothly in the
initial stage then the reactivity rapidly dropped with the
color change from pale yellow to black. These results
indicated that the LUMO energy of a,b-unsaturated amide
and ester are low enough to be promoted epoxidation by
Ln–BINOL–Ph3AsvO complex, however, a,b-unsatu-
rated ester promotes deactivation of the lanthanide catalyst.
To get insight about these results, we examined the effect of
aging of the catalysts (Table 7). When the catalyst was aged
for 3 h by adding 1 equiv. of saturated ester 29 (entry 3),
nearly same result was obtained compared as that of the
control experiment (entry 2). When a,b-unsaturated ester
27 was added to the reaction (entries 4, 5), however, a
Table 7. The effect of aging of the catalyst
Scheme 7.
Entry
Additive
Aging time
(h)
Yield
(%)
ee
(%)
1
2
3
4
5
–
–
0
3
3
3
0
99
99
99
32 (8)a
62 (0)a
99.5
99.0
99.2
97.1
99.1
Ph(CH2)4CO2Me (29)
Ph(CH2)2CHvCHCO2Me (27)
Ph(CH2)2CHvCHCO2Me (27)
a
Scheme 8.
Yield of the a,b-epoxy ester 28.

T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
10491
decrease in the catalyst activity was observed. These
experimental results suggest that a,b-unsaturated ester
might form an unfavorable complex with the catalyst,
resulting in decreased catalyst activity. Although detailed
investigation will be necessary, these finding should be
useful to design a novel chiral catalyst system to further
improve the epoxidation.
solvents under an argon atmosphere, unless otherwise
stated. Tetrahydrofuran (THF) was distilled from
sodium benzophenone ketyl. All Ln(O-i-Pr)3 were
purchased from Kojundo Chemical Laboratory Co.,
LTD., 5-1-28, Chiyoda, Sakado-shi, Saitama 350-0214,
Japan (fax: þ81-492-84-1351). Powdered molecular
sieve 4A (MS 4A) was purchased from Fluka (catalog
No. 69836) and used for the epoxidation without drying,
unless otherwise stated. Other reagents were purified by
the usual methods.
3. Conclusions
4.2. General procedure for the preparation of
a,b-unsaturated carboxylic acid imidazolide 7
We developed the first catalytic asymmetric epoxidation of
a,b-unsaturated carboxylic acid derivatives with broad
substrate generality via a 1,4-addition of peroxide using
a,b-unsaturated carboxylic acid imidazolide as a substrate
and the novel lanthanide–BINOL complex as a catalyst.
Further, a,b-unsaturated simple amides were good sub-
strates for the epoxidation, affording high enantiomeric
excess (up to .99% ee). Moreover, the obtained highly
optically active epoxides were successfully transformed into
many types of useful chiral compounds such as a,b-epoxy
esters, a,b-epoxy amides, a,b-epoxy aldehydes, a,b-epoxy
b-keto ester, and a- and b-hydroxy carbonyl compounds.
To predict the substrate reactivity, AM1 semiempirical
molecular orbital calculation and B3LYP hybrid density
functional studies were performed. Although there are some
exceptions and further precise calculations are necessary to
establish a reliable prediction system, these simple calcu-
lations might be useful for initial predictions. Further
investigation concerning the development of a catalyst with
higher activity, the clarification of the reaction mechanism,
and applications to a catalytic asymmetric synthesis of
biologically active compounds including a tandem process
is ongoing.
1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydro-
chloride (719 mg, 3.75 mmol) was added to a stirred
solution of cinnamic acid (445 mg, 3 mmol) and 4-phenyl-
imidazole (433 mg, 3 mmol) in DMF (15 mL) at room
temperature. After stirring for 12 h at the same temperature,
the reaction mixture was poured into saturated aqueous
ammonium chloride. The resulting mixture was extracted
with ethyl acetate (200 mL) and ether (100 mL). The
combined organic layers were washed with H2O (30 mL)
followed by brine (30 mL) and dried over Na2SO4. After
concentration in vacuo, the resulting solid was washed with
cold ether to afford imidazolide 7e (734 mg 90%) as a
yellow solid.
Imidazolides 7b–p were synthesized according to the
general procedure. Compounds 5,22 7a,23 and 1022 were
synthesized according to the reported procedure.
4.2.1. 2-Methyl-1-[(2E)-1-oxo-3-phenyl-2-propenyl]-1H-
imidazole (7b). White solid; mp 84–858C; IR (KBr) n
3392, 1709, 1618, 1404, 1286, 1254, 1134, 994, 775, 762,
1
679 cm21; H NMR (CDCl3) d 2.73 (s, 3H), 6.96 (d, J¼
1.6 Hz, 1H), 7.05 (d, J¼15.3 Hz, 1H), 7.39 (d, J¼1.6 Hz,
1H), 7.43–7.49 (m, 3H), 7.62–7.63 (m, 2H), 7.97 (d, J¼
15.3 Hz, 1H); 13C NMR (CDCl3) d 17.4, 116.7, 116.9,
128.4, 128.6 (£2), 129.1 (£2), 131.4, 133.8, 148.5, 149.0,
163.7; MS m/z 212 (Mþ). HRMS calcd for C13H12N2O
(Mþ): 212.0950. Found 212.0959.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 410
Fourier transform infrared spectrophotometer. NMR spectra
were recorded on a JEOL JNM-LA500 spectrometer,
1
4.2.2. 4-Methyl-1-[(2E)-1-oxo-3-phenyl-2-propenyl]-1H-
imidazole (7c). White solid; mp 145–1488C; IR (KBr) n
3128, 1690, 1626, 1484, 1396, 1376, 1285, 1263, 1174, 987,
763 cm21; 1H NMR (CDCl3) d 2.28 (d, J¼1.2 Hz, 3H), 7.03
(d, J¼15.6 Hz, 1H), 7.33 (br-t, 1H), 7.44–7.47 (m, 3H),
7.63–7.65 (m, 2H), 8.04 (d, J¼15.6 Hz, 1H), 8.21 (d, J¼
1.2 Hz, 1H); 13C NMR (CDCl3) d 13.6, 112.4, 115.0, 128.6
(£2), 129.1 (£2), 131.5, 133.7, 135.7, 140.7, 149.2, 161.5;
MS m/z 212 (Mþ). HRMS calcd for C13H12N0O (Mþ):
212.0950. Found 212.0956.
operating at 500 MHz for H NMR and 125.65 MHz for
13C NMR. Chemical shifts in CDCl3 were reported down-
1
field from TMS (¼0 ppm) for H NMR. For 13C NMR,
chemical shifts were reported downfield from TMS
(¼0 ppm) or on a scale relative to CHCl3 (77.00 ppm for
13C NMR) as an internal reference. Chemical shifts in
DMSO-d6 were reported on a scale relative to DMSO
(2.50 ppm for 1H NMR and 39.5 ppm for 13C NMR).
Optical rotations were measured on a JASCO P-1010
polarimeter. EI mass spectra were measured on a JEOL
JMS-DX303 or JMS-BU20 GCmate. ESI mass spectra were
measured on a Waters micromass ZQ Column chroma-
tography was performed with silica gel Merck 60 (230–400
mesh ASTM). The enantiomeric excess was determined by
HPLC analysis. HPLC was performed on JASCO HPLC
systems consisting of the following: pump, 880-PU or
PU-980; detector, 875-UV or UV-970, measured at 254 or
280 nm; column, DAICEL CHIRALPAK AD, AS, AS-H,
or OD; mobile phase, hexane-2-propanol; flow rate,
0.4–1.0 mL/min. Reactions were performed in dry
4.2.3. 1-[(2E)-1-Oxo-3-phenyl-2-propenyl]-2-phenyl-1H-
imidazole (7d). White-yellow solid; mp 92–92.58C; IR
(KBr) n 3383, 1698, 1617, 1465, 1378, 1352, 1230, 1202,
1
1087, 995, 757, 700 cm21; H NMR (CDCl3) d 6.48 (d,
J¼15.3 Hz, 1H), 7.17 (d, J¼1.6 Hz, 1H), 7.17–7.19 (m,
2H), 7.30–7.46 (m, 6H), 7.60–7.62 (m, 2H), 7.67 (d, J¼
1.6 Hz, 1H), 7.82 (d, J¼15.3 Hz, 1H); 13C NMR (CDCl3) d
118.5, 119.3, 128.4 (£2), 128.6 (£2), 128.9 (£2), 129.2,
129.5 (£2), 129.6, 131.3, 131.5, 133.7, 147.7, 148.1, 164.1;

10492
T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
MS m/z 274 (Mþ). HRMS calcd for C18H14N2O (Mþ):
274.1106. Found 274.1104.
4.2.9. 1-[(2E)-1-Oxo-5-phenyl-2-pentenyl]-4-phenyl-1H-
imidazole (7j). White solid; mp 140–1448C; IR (KBr) n
1
1698, 1635, 1496, 1396, 1196, 758, 697, 409 cm21; H
4.2.4. 1-[(2E)-1-Oxo-3-phenyl-2-propenyl]-4-phenyl-1H-
imidazole (7e). Yellow solid; mp 230–2328C; IR (KBr) n
1687, 1621, 1495, 1395, 1290, 1236, 1188, 988, 753,
NMR (CDCl3) d 2.73 (ddd, J¼14.5, 7.4, 1.5 Hz, 2H), 2.90
(t, J¼7.4 Hz, 2H), 6.48 (dd, J¼15.3, 1.5 Hz, 1H), 7.21–7.44
(m, 9H), 7.76 (d, J¼1.2 Hz, 1H), 7.82 (m, 2H), 8.15 (d, J¼
1.2 Hz, 1H); 13C NMR (CDCl3) d 34.1, 34.4, 111.0, 119.6,
125.4 (£2), 126.5, 127.9, 128.4 (£2), 128.6 (£2), 128.7
(£2), 132.6, 136.3, 140.1, 153.9, 161.2; MS m/z 302 (Mþ).
HRMS calcd for C20H18N2O (Mþ): 302.1419. Found
302.1418.
1
694 cm21; H NMR (CDCl3) d 7.11 (d, J¼15.6 Hz, 1H),
7.31–7.50 (m, 6H), 7.67–7.69 (m, 2H), 7.86–7.87 (m, 2H),
7.91 (d, J¼1.6 Hz, 1H), 8.11 (d, J¼15.6 Hz, 1H), 8.35 (d,
J¼1.6 Hz, 1H); 13C NMR (CDCl3) d 111.2, 114.5, 125.5
(£2), 128.1, 128.8 (£2), 128.9 (£2), 129.9 (£2), 131.8,
132.4, 133.7, 136.3, 143.6, 150.0, 161.6; MS m/z 274 (Mþ).
HRMS calcd for C18H14N2O (Mþ): 274.1106. Found
274.1102.
4.2.10. 1-[(2E,6Z)-1-Oxo-2,6-octadienyl]-4-phenyl-1H-
imidazole (7l). White solid; mp 96–1028C; IR (KBr) n
3132, 3008, 1702, 1642, 1503, 1398, 1312, 1295, 1254,
1
4.2.5. 1-[(2E)-1-Oxo-3-phenyl-2-propenyl]-1H-benzo-
imidazole (7f). White solid; mp 233–2348C; IR (KBr) n
3091, 1701, 1622, 1506, 1478, 1451, 1319, 1289, 1275,
1225, 1207, 1151, 994, 762 cm21; 1H NMR (CDCl3) d 7.24
(d, J¼15.3 Hz, 1H), 7.43–7.50 (m, 5H), 7.68–7.70 (m, 2H),
7.84 (d, J¼7.0 Hz, 1H), 8.11 (d, J¼15.3 Hz, 1H), 8.34 (d,
J¼7.0 Hz, 1H), 8.57 (s, 1H); 13C NMR (CDCl3) d 115.7,
115.8, 120.6, 125.1, 125.8, 128.7 (£2), 129.2 (£2), 131.5,
131.9, 133.8, 140.7, 144.1, 148.9, 162.9; MS m/z 248 (Mþ).
Anal. calcd for C16H12N2O: C, 77.40; H, 4.87; N, 11.28.
Found: C, 77.24; H, 5.01; N, 11.05.
1200, 978, 758, 689 cm21; H NMR (CDCl3) d 1.64–1.66
(m, 3H), 2.32–2.35 (m, 2H), 2.45–2.49 (m, 2H), 5.39–5.41
(m, 1H), 5.55–5.59 (m, 1H), 6.56 (dt, J¼15.3, 1.5 Hz, 1H),
7.30–7.43 (m, 3H), 7.41 (dt, J¼15.3, 7.0 Hz, 1H), 7.82 (d,
J¼1.2 Hz, 1H), 7.82–7.84 (m, 2H), 8.24 (d, J¼1.2 Hz, 1H);
13C NMR (CDCl3) d 12.9, 25.2, 32.8, 111.1, 119.1, 125.4
(£2), 125.8, 127.9, 128.2, 128.7 (£2), 132.6, 136.3, 143.7,
154.9, 161.3; MS m/z 266 (Mþ). HRMS calcd for
C17H18N2O (Mþ): 266.1419. Found 266.1416.
4.2.11. 1-[(2E,6E)-1-Oxo-2,6-octadienyl]-4-phenyl-1H-
imidazole (7m). White-yellow solid; mp 112–1198C; IR
(KBr) n 3133, 2934, 1698, 1635, 1499, 1395, 1293, 1253,
4.2.6. 1-[(2E)-3-(4-Chlorophenyl)-1-oxo-2-propenyl]-4-
phenyl-1H-imidazole (7g). White-yellow solid; mp 269–
2708C; IR (KBr) n 3127, 1697, 1620, 1492, 1409, 1390,
1
1201, 983, 964, 758, 691 cm21; H NMR (CDCl3) d 1.68
(dd, J¼6.1, 1.2 Hz, 3H), 2.23–2.27 (m, 2H), 2.42–2.47
(m, 2H), 5.40–5.45 (m, 1H), 5.49–5.56 (m, 1H), 6.56 (dt,
J¼15.3, 1.5 Hz, 1H), 7.29–7.42 (m, 3H), 7.39 (dt, J¼15.3,
7.0 Hz, 1H), 7.82 (d, J¼1.2 Hz, 1H), 7.82–7.84 (m, 2H),
8.24 (d, J¼1.2 Hz, 1H); 13C NMR (CDCl3) d 17.9, 30.8,
32.9, 111.1, 119.0, 125.3 (£2), 126.8, 127.9, 128.7 (£2),
129.0, 132.5, 136.4, 143.6, 155.0, 161.3; MS m/z 266 (Mþ).
HRMS calcd for C17H18N2O (Mþ): 266.1419. Found
266.1424.
1
1190, 993, 980, 823, 784, 762, 694, 419 cm21; H NMR
(DMSO-d6) d 7.27–7.31 (m, 1H), 7.40–7.43 (m, 2H), 7.58
(m, 2H), 7.72 (d, J¼15.6 Hz, 1H), 7.90–7.92 (m, 2H), 7.98
(m, 2H), 8.01 (d, J¼15.6 Hz, 1H), 8.42 (s, 1H), 8.81 (s, 1H);
13C NMR (DMSO-d6) d 112.1, 117.1, 125.1 (£2), 127.7,
128.8 (£2), 129.2 (£2), 131.0 (£2), 132.8, 133.0, 136.1,
137.9, 142.4, 147.0, 161.8; MS m/z 308 (Mþ). HRMS calcd
for C18H13ClN2O (Mþ): 308.0716. Found 308.0714.
4.2.7. 1-[(2E)-3-(4-Bromophenyl)-1-oxo-2-propenyl]-4-
methyl-1H-imidazole (7h). Yellow solid; mp 203–2058C;
IR (KBr) n 3127, 1692, 1624, 1585, 1483, 1406, 1392, 1278,
4.2.12. 1-[(2E,6Z)-1-Oxo-7-phenyl-2,6-heptadienyl]-4-
phenyl-1H-imidazole (7n). White-yellow solid; mp 117–
1198C; IR (KBr) n 3127, 1699, 1643, 1498, 1401, 1254,
1
1
1261, 1175, 987, 820, 781, 403 cm21; H NMR (CDCl3) d
1204, 758, 695 cm21; H NMR (CDCl3) d 2.52–2.56 (m,
2.28 (d, J¼1.2 Hz, 3H), 7.04 (d, J¼15.6 Hz, 1H), 7.33 (dd,
J¼1.2, 1.2 Hz, 1H), 7.50–7.52 (m, 2H), 7.58–7.60 (m, 2H),
7.97 (d, J¼15.6 Hz, 1H), 8.24 (d, J¼1.2 Hz, 1H); 13C NMR
(CDCl3) d 13.6, 112.4, 115.5, 126.0, 130.0 (£2), 132.4 (£2),
132.6, 135.6, 140.7, 147.8, 161.3; MS m/z 292 (Mþ), 290
(Mþ). Anal. calcd for C13H11BrN2O: C, 53.63; H, 3.81; N,
9.62. Found: C, 53.61; H, 3.91; N, 9.39.
2H), 2.61–2.65 (m, 2H), 5.65 (dt, J¼11.6, 7.0 Hz, 1H), 6.50
(dt, J¼15.3, 1.6 Hz, 1H), 6.54 (d, J¼11.6 Hz, 1H), 7.29–
7.42 (m, 9H), 7.77 (d, J¼1.2 Hz, 1H), 7.81–7.83 (m, 2H),
8.17 (d, J¼1.2 Hz, 1H); 13C NMR (CDCl3) d 26.6, 32.9,
111.1, 119.3, 125.4 (£2), 127.0, 127.9, 128.4 (£2), 128.7
(£2), 128.7 (£2), 130.2, 130.6, 132.6, 136.4, 137.1, 143.7,
154.3, 161.2; MS m/z 328 (Mþ). HRMS calcd for
C22H20N2O (Mþ): 328.1576. Found 328.1577.
4.2.8. 1-[(2E)-3-(4-Methoxyphenyl)-1-oxo-2-propenyl]-4-
phenyl-1H-imidazole (7i). White-yellow solid; mp 188–
1898C; IR (KBr) n 3120, 1695, 1621, 1560, 1572, 1511,
1294, 1250, 1174, 997, 978, 834, 766, 697 cm21; 1H NMR
(CDCl3) d 3.88 (s, 3H), 6.96 (d, J¼15.6 Hz, 1H), 6.97
(m, 2H), 7.30–7.44 (m, 3H), 7.63 (m, 2H), 7.85–7.90
(m, 2H), 7.90 (d, J¼1.2 Hz, 1H), 8.06 (d, J¼15.6 Hz, 1H),
8.33 (d, J¼1.2 Hz, 1H); 13C NMR (CDCl3) d 55.5, 111.2,
111.8, 114.7 (£2), 125.4 (£2), 126.5, 127.9, 128.7 (£2),
130.8 (£2), 132.7, 136.3, 143.6, 149.6, 161.9, 162.6; MS m/z
304 (Mþ). Anal. calcd for C19H16N2O2: C, 74.98; H, 5.30;
N, 9.20. Found: C, 75.01; H, 5.38; N, 9.09.
4.2.13. 1-[(2E)-1,7-Dioxo-2-octenyl]-4-phenyl-1H-imida-
zole (7o). White-yellow solid; IR (KBr) n 3136, 1707, 1697,
1637, 1316, 1295, 1252, 1199, 989, 858, 767, 698 cm21 1H
NMR (CDCl3) d 1.84 (tt, J¼7.0 Hz, 7.0 Hz, 2H), 2.16 (s,
3H), 2.38–2.42 (m, 2H), 2.54 (t, J¼7.0 Hz, 2H), 6.57 (dt,
J¼15.3, 1.6 Hz, 1H), 7.30–7.43 (m, 3H), 7.38 (dt, J¼15.3,
7.0 Hz, 1H), 7.82 (d, J¼1.5 Hz, 1H), 7.82–7.84 (m, 2H),
8.25 (d, J¼1.5 Hz, 1H); 13C NMR (CDCl3) d 21.6, 30.0, 32.0,
42.4, 111.0, 119.3, 125.4 (£2), 127.9, 128.7 (£2), 132.5,
136.4, 143.7, 154.3, 161.2, 207.7; MS m/z 282 (Mþ). HRMS
calcd for C17H18N2O2 (Mþ): 282.1368. Found 282.1365.

T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
10493
4.2.14. 1-[(2E)-3-Cyclohexyl-1-oxo-2-propenyl]-1H-imi-
dazole (7p). White solid; mp 147–1498C; IR (KBr) n 3129,
2931, 2855, 1698, 1627, 1495, 1389, 1279, 1246, 1197,
724 cm21; 1H NMR (CDCl3) d 3.47 (d, J¼1.4 Hz, 1H), 3.83
(s, 3H), 4.07 (d, J¼1.4 Hz, 1H), 7.15–7.17 (m, 2H), 7.49–
7.51 (m, 2H); 13C NMR (CDCl3) d 52.7, 56.6, 57.4, 123.1,
127.4 (£2), 131.9 (£2), 134.0, 168.3; MS m/z 255 (Mþ),
200, 198. Anal. calcd for C10H9BrO3: C, 46.72; H, 3.53.
Found: C, 46.47; H, 3.57; [a]2D5¼2118.0 (c 0.79, CHCl3,
89% ee). The enantiomeric excess was determined by chiral
stationary-phase HPLC analysis (DAICEL CHIRALCEL
OD, i-PrOH/hexane 1:9, flow rate 0.5 mL/min, tR 15.1 min
(major-isomer) and 18.8 min (minor-isomer), detection at
254 nm).
1
1177, 987, 762, 692 cm21; H NMR (CDCl3) d 1.19–1.40
(m, 6H), 1.71–1.88 (m, 4H), 2.32–2.35 (m, 1H), 6.48 (dd,
J¼15.3, 1.2 Hz, 1H), 7.30–7.43 (m, 3H), 7.36 (dd, J¼15.3,
7.0 Hz, 1H), 7.82 (d, J¼1.2 Hz, 1H), 7.82–7.84 (m, 2H),
8.24 (d, J¼1.2 Hz, 1H); 13C NMR (CDCl3) d 25.6, 25.8,
31.5, 41.3, 111.1, 116.4, 125.4 (£2), 127.9, 128.7 (£2),
132.6, 136.4, 143.7, 160.4, 161.7; MS m/z 280 (Mþ). HRMS
calcd for C18H20N2O: 280.1576. Found 280.1574.
4.3. General procedure for the catalytic asymmetric
epoxidation of a,b-unsaturated carboxylic acid
imidazolide 7 to synthesize the a,b-epoxy esters 8
4.3.4. Methyl (2R,3S)-3-(4-methoxyphenyl)oxiranecarb-
oxylate (8i).7c Because of the instability of the compound 8i
against acidic conditions, special work-up and purification
methods were necessary to minimize the decomposition
of 8i to the corresponding a,b-dihydroxy ester. After
conversion of the peroxy ester to the methyl ester 8i, the
reaction mixture was cooled at 08C, diluted with ethyl
acetate (5 mL), and then quenched by the addition of
aqueous 0.01 M HCl solution (10 mL) to the mixture. The
resulting mixture was poured into water (5 mL) and
extracted with ethyl acetate (2£15 mL). The combined
organic layers were washed with 2% aqueous sodium
thiosulfate (5 mL) and brine (5 mL), and dried over Na2SO4.
After concentration in vacuo, the residue was purified by
flash column chromatography (neutral SiO2, hexane/ethyl
acetate/triethylamine 200:10:1) to give 8i in 80% isolated
yield as a colorless oil. [a]2D5¼2144.8 (c 0.63, CHCl3, 91%
ee). The enantiomeric excess was determined by chiral
stationary-phase HPLC analysis (DAICEL CHIRALCEL
OD, i-PrOH/hexane 1:9, flow rate 1.0 mL/min, tR 8.5 min
(2R,3S)-isomer and 12.1 min (2S,3R)-isomer, detection at
254 nm).
A solution of La(O-i-Pr)3 (0.125 mL, 0.025 mmol, 0.2 M
solution in THF) was added to a mixture of (S)-BINOL
(7.2 mg, 0.025 mmol), triphenylarsine oxide (8.1 mg,
0.025 mmol) and MS 4A (250 mg) in dry THF (2.5 mL)
at room temperature. After stirring for 45 min at the same
temperature, TBHP (0.12 mL, 0.6 mmol, 5 M solution in
decane) was added. After stirring for 10 min, imidazolide 7e
(68.6 mg, 0.25 mmol) was added directly and the mixture
was stirred at room temperature. After the starting material
was completely consumed, excess MeOH (0.5 mL) was
added to the reaction mixture and the resulting mixture was
stirred for 3 h, and then quenched by the addition of 1%
aqueous citric acid solution (2.5 mL) at 08C. The mixture
was extracted with ethyl acetate (2£10 mL) and the
combined organic layers were washed with 2% aqueous
sodium thiosulfate (5 mL) and brine (5 mL), and dried over
Na2SO4. After concentration in vacuo, the residue was
purified by flash column chromatography (SiO2, hexane/
ethyl acetate 50:1) to give epoxy ester 8a (38.5 mg, 86%) as
a colorless oil.
4.3.5. Methyl (2R,3S)-3-(2-phenylethyl)oxiranecarboxyl-
ate (8j). Colorless oil; IR (neat) n 3027, 2952, 1752, 1453,
;
1291, 1029, 700 cm21 1H NMR (CDCl3) d 1.86–2.01
4.3.1. Methyl (2R,3S)-3-phenyloxiranecarboxylate
(8a).7a,b White solid; [a]D24¼2111.8 (c 1.17, CHCl3, 92%
ee). The enantiomeric excess was determined by chiral
stationary-phase HPLC analysis (DAICEL CHIRALPAK
AD, i-PrOH/hexane 2:98, flow rate 0.4 mL/min, tR 28.6 min
(2S,3R)-isomer and 30.6 min (2R,3S)-isomer, detection at
254 nm).
(m, 2H), 2.73–2.86 (m, 2H), 3.20 (ddd, J¼6.4, 4.6, 1.8 Hz,
1H), 3.21 (4.07 (d, J¼1.8 Hz, 1H), 3.76 (s, 3H), 7.18–7.31
(m, 5H); 13C NMR (CDCl3) d 31.9, 33.2, 52.4, 53.1, 57.8,
126.3, 128.3 (£2), 128.6 (£2), 140.5, 169.5; MS m/z 206
(Mþ). HRMS calcd for C12H14O3 (Mþ): 206.0943. Found
206.0945; [a]2D5¼233.5 (c 0.82, CHCl3, 83% ee). The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALPAK AD,
i-PrOH/hexane 2:98, flow rate 1.0 mL/min, tR 9.7 min
(2R,3S)-isomer and 10.7 min (2S,3R)-isomer, detection at
254 nm).
4.3.2. Methyl (2R,3S)-3-(4-chlorophenyl)oxiranecarb-
oxylate (8g). White-yellow solid; mp 59–628C; IR (neat)
n 3034, 1753, 1496, 1427, 1340, 1213, 1090, 834, 802,
1
728 cm21; H NMR (CDCl3) d 3.47 (dd, J¼1.9, 1.5 Hz,
1H), 3.83 (s, 3H), 4.08 (d, J¼1.5 Hz, 1H), 7.21–7.23 (m,
2H), 7.33–7.35 (m, 2H); 13C NMR (CDCl3) d 52.7, 56.6,
57.3, 127.1 (£2), 128.9 (£2), 133.4, 134.9, 168.3; MS
m/z 212 (Mþ), 155. HRMS calcd for C10H9ClO3 (Mþ):
212.0240. Found 212.0246; [a]2D3¼2148.7 (c 1.03, CHCl3,
93% ee). The enantiomeric excess was determined by chiral
stationary-phase HPLC analysis (DAICEL CHIRALCEL
OD, i-PrOH/hexane 1:9, flow rate 0.5 mL/min, tR 14.7 min
(major-isomer) and 17.7 min (minor-isomer), detection at
254 nm).
4.3.6. Methyl (2R,3S)-3-(4-pentenylbutyl)oxiranecarb-
oxylate (8k). Pale yellow oil; IR (neat) n 3025, 2935,
1
2858, 1755, 1453, 1291, 1250, 1030, 700 cm21; H NMR
(CDCl3) d 7.34 (m, 2H), 7.24 (m, 3H), 3.84 (s, 3H), 3.29 (d,
J¼2 Hz, 1H), 3.22 (ddd, J¼6, 5, 2 Hz, 1H), 2.69 (t, J¼
7.5 Hz, 2H), 1.78–1.55 (m, 6H); 13C NMR (CDCl3) d
169.7, 142.1, 128.34 (£2), 128.29 (£2), 125.8, 58.4, 52.9,
52.4, 35.7, 31.3, 31.0, 25.3; EI-MS m/z 234 (Mþ); [a]D24¼
224.6 (c 1.7, CHCl3, 99% ee). The enantiomeric excess was
determined by chiral stationary-phase HPLC analysis
(DAICEL CHIRALPAK AD-H, i-PrOH/hexane 1:99, flow
rate 1.0 mL/min, tR 12.1 min (2R,3S)-isomer and 14.0 min
(2S,3R)-isomer, detection at 254 nm).
4.3.3. Methyl (2R,3S)-3-(4-bromophenyl)oxiranecarb-
oxylate (8h). White-yellow solid; mp 74–758C; IR (neat)
n 3033, 1752, 1493, 1425, 1339, 1214, 1071, 832, 801,

10494
T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
4.3.7. Methyl (2R,3S)-3-[(3Z)-3-pentenyl]oxiranecarb-
oxylate (8l). Colorless oil; IR (neat) n 3015, 2953, 1755,
after conversion to the corresponding 4-methoxybenzyl
ester.
1
1446, 1291, 1206, 1030, 711 cm21; H NMR (CDCl3) d
1.62 (ddd, J¼6.7, 1.8, 0.9 Hz, 3H), 1.64–1.73 (m, 2H),
2.21–2.25 (m, 2H), 3.18 (ddd, J¼6.1, 5.2, 1.8 Hz, 1H), 3.25
(d, J¼1.8 Hz, 1H), 3.78 (s, 3H), 5.36–5.42 (m, 1H), 5.44–
5.56 (m, 1H); 13C NMR (CDCl3) d 12.7, 23.0, 31.3, 52.4,
53.0, 58.1, 125.4, 128.4, 169.7; MS m/z 149, 137, 121.
HRMS calcd for C9H13O3 (Mþ21): 169.0865. Found
169.0861; [a]2D1¼214.8 (c 1.09, CHCl3, 86% ee). The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALCEL OD, i-PrOH/
hexane 1:9, flow rate 0.5 mL/min, tR 14.5 min (minor-
isomer) and 23.7 min (major-isomer), detection at 254 nm)
after conversion to the corresponding 4-methoxybenzyl
ester.
4.3.11. Methyl (2R,3S)-3-cyclohexyloxiranecarboxylate
(8p).24 Colorless oil; [a]D25¼224.8 (c 1.27, CHCl3, 88% ee).
The enantiomeric excess was determined by chiral station-
ary-phase HPLC analysis (DAICEL CHIRALPAK AD,
i-PrOH/hexane 1:9, flow rate 0.5 mL/min, tR 15.5 min
(2S,3R)-isomer and 17.5 min (2R,3S)-isomer, detection at
254 nm) after conversion to the corresponding 4-methoxy-
benzyl ester.
4.3.12. tert-Butyl (2R,3S)-3-phenylperoxyglycidate (6a).
After completion of the epoxidation, the reaction was
quenched by the addition of 1% aqueous citric acid solution
(2.5 mL) at 08C. The mixture was extracted with ethyl
acetate (2£10 mL) and the combined organic layers were
washed with brine (5 mL) and dried over Na2SO4. After
concentration in vacuo, the residue was purified by flash
column chromatography (SiO2, hexane/ethyl acetate 50:1)
to give 6a (51.0 mg, 86%) as a white solid: mp 86–888C; IR
(neat) n 2983, 1787, 1458, 1419, 1367, 1248, 1187, 1131,
4.3.8. Methyl (2R,3S)-3-[(3E)-3-pentenyl]oxiranecarb-
oxylate (8m). Colorless oil; IR (neat) n 2938, 2856, 1755,
1448, 1291, 1206, 1029, 968, 471 cm21; 1H NMR (CDCl3)
d 1.62 (dd, J¼6.1 Hz, 1.2 Hz, 3H), 1.60–1.73 (m, 2H),
2.12–2.20 (m, 2H), 3.17 (ddd, J¼6.1, 5.2, 1.8 Hz, 1H), 3.25
(d, J¼1.8 Hz, 1H), 3.78 (s, 3H), 5.36–5.42 (m, 1H), 5.44–
5.56 (m, 1H); 13C NMR (CDCl3) d 17.8, 28.7, 31.4, 52.4,
53.0, 58.1, 126.4, 129.3, 169.7; MS m/z 149, 137, 121, 120.
HRMS calcd for C6H9O3 (Mþ2C3H5): 129.0552. Found
129.0562; [a]2D3¼221.2 (c 0.9, CHCl3, 79% ee). The
enantiomeric excess of 6n was determined by chiral
stationary-phase HPLC analysis (DAICEL CHIRALPAK
AD, i-PrOH/hexane 1:9, flow rate 0.5 mL/min, tR 14.5 min
(minor-isomer) and 20.4 min (major-isomer), detection at
254 nm) after conversion to the corresponding 4-methoxy-
benzyl ester.
1
752, 697 cm21; H NMR (CDCl3) d 1.34 (s, 9H), 3.52 (d,
J¼2.0 Hz, 1H), 4.14 (d, J¼2.0 Hz, 1H), 7.23–7.28 (m, 2H),
7.33–7.39 (m, 3H); 13C NMR (CDCl3) d 26.1 (£3), 54.9,
58.1, 84.5, 125.8 (£2), 128.7 (£2), 129.2, 134.4, 165.8; MS
m/z 236 [Mþ]; [a]D27¼2167.2 (c 0.75, CHCl3, 94% ee).
HRMS calcd for C13H16O4 (Mþ): 236.1049. Found
236.1055.
4.3.13. The absolute configurations of 8. The absolute
configurations of the epoxy ester 8a,7a,b 8i,7c and 8p24 were
determined by comparing the measured optical rotations
with the reported ones. The absolute configuration of 8g was
determined by comparing the measured optical rotation with
the reported rotation25 after converting into the correspond-
ing b-hydroxy ester. The absolute configuration of 8k was
determined by Mosher’s method after conversion to the
corresponding b-hydroxy ester.26 The absolute configu-
rations of 8l and 8m were determined by comparing the
measured optical rotation with the reported rotation27 after
converting into methyl 3-hydroxyoctanoate.
4.3.9. Methyl (2R,3S)-3-[(3Z)-4-phenyl-3-butenyl]oxirane-
carboxylate (8n). Colorless oil; IR (neat) n 3019, 2952,
1
1753, 1446, 1291, 1206, 1029, 770, 701 cm21; H NMR
(CDCl3) d 1.70–1.84 (m, 2H), 2.49–2.54 (m, 2H), 3.19
(ddd, J¼6.4, 4.9, 1.9 Hz, 1H), 3.25 (d, J¼1.9 Hz, 1H), 3.76
(s, 3H), 5.65 (dt, J¼11.6, 7.3 Hz, 1H), 6.48 (d, J¼11.6 Hz,
1H), 7.22–7.26 (m, 2H), 7.32–7.35 (m, 3H); 13C NMR
(CDCl3) d 24.8, 31.6, 52.4, 52.9, 57.9, 126.8, 128.2 (£2),
128.7 (£2), 130.2, 130.4, 137.1, 169.5; MS m/z 232 (Mþ).
HRMS calcd for C14H16O3 (Mþ): 232.1099. Found
232.1098; [a]2D2¼213.7 (c 0.54, CHCl3, 82% ee). The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALCEL OD, i-PrOH/
hexane 1:9, flow rate 0.5 mL/min, tR 14.9 min (minor-
isomer) and 25.8 min (major-isomer), detection at 254 nm).
4.4. General procedure for the catalytic asymmetric
epoxidation of b-alkyl type a,b-unsaturated amides
(condition A)
A solution of Sm(O-i-Pr)3 (0.5 mL, 0.05 mmol, 0.1 M
solution in THF) was added to a mixture of (S)-BINOL
(14.3 mg, 0.05 mmol), triphenylarsine oxide (16.1 mg,
0.05 mmol) and MS 4A (500 mg) in dry THF (5 mL) at
room temperature. After stirring for 45 min at the same
temperature, TBHP (0.12 mL, 0.6 mmol, 5 M solution in
decane) was added. After stirring for 10 min, amide 20a
(94.6 mg, 0.5 mmol) was added directly and the mixture
was stirred at room temperature. After complete consump-
tion of the starting material (8 h), the reaction mixture was
diluted with ethyl acetate (20 mL) and quenched with 2%
aqueous citric acid (5 mL). The water layer was extracted
with ethyl acetate (10 mL), and the combined organic layers
were washed with brine (10 ml) and dried over Na2SO4.
After concentration in vacuo, the residue was purified by
flash chromatography (SiO2, hexane/ethyl acetate¼4:1–3:1)
4.3.10. Methyl (2R,3S)-3-(4-oxopentyl)oxiranecarboxyl-
ate (8o). Colorless oil; IR (neat) n 2955, 1751, 1714, 1488,
1361, 1293, 1207 cm21; 1H NMR (CDCl3) d 1.49–1.58 (m,
1H), 1.69–1.82 (m, 3H), 2.15 (s, 1H), 2.52 (t, J¼7.3 Hz,
2H), 3.16 (ddd, J¼6.7, 4.0, 1.8 Hz, 1H), 3.22 (d, J¼1.8 Hz,
1H), 3.78 (s, 3H); 13C NMR (CDCl3) d 19.8, 30.0, 30.6,
42.6, 52.4, 52.6, 58.1, 169.5, 208.0; MS m/z 186 (Mþ).
HRMS calcd for C9H14O4 (Mþ): 186.0892. Found
186.0888; [a]2D2¼210.3 (c 0.26, CHCl3, 81% ee). The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALCEL OD, i-PrOH/
hexane 1:3, flow rate 0.5 mL/min, tR 19.7 min (minor-
isomer) and 30.3 min (major-isomer), detection at 254 nm)

T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
10495
to give epoxy amide 21a (101.9 mg, 99%) as a white yellow
solid.
55.5, 59.1, 126.2, 128.3 (£2) 128.5 (£2) 140.5, 167.4;
ESI-MS m/z 296 (MþNaþ). HRMS calcd for C17H23NO2
(Mþ): 273.1729. Found 273.1723. The enantiomeric excess
was determined by chiral stationary-phase HPLC analysis
(DAICEL CHIRALPAK AS-H, i-PrOH/hexane 1:4, flow
rate 0.5 mL/min, tR 24.1 min (minor isomer) and 48.2 min
(major isomer), detection at 254 nm); [a]2D8¼þ0.77 (c 0.78,
CHCl3, .99% ee).
4.4.1. (2R,3S)-3-Phenethyloxirane-2-carboxlic acid
methyamine (21a). White yellow solid; IR (KBr) n 3294,
1
3124, 1656, 1580, 1450, 1267, 902, 742, 695 cm21; H
NMR (CDCl3) d 1.80–1.81 (m, 1H), 1.99–2.06 (m, 4H),
2.73–2.83 (m, 2H), 2.79 (d, J¼5.0 Hz, 3H), 2.96 (ddd,
J¼6.6, 4.3, 2.1 Hz, 1H), 3.23 (d, J¼2.1 Hz, 1H), 6.09 (br-s,
1H), 7.19–7.23 (m, 3H), 7.27–7.33 (m, 2H); 13C NMR
(CDCl3) d 25.7, 32.0, 33.7, 55.7, 59.2, 126.5, 128.6 (£2),
128.8 (£2), 140.7, 169.2; ESI-MS m/z 228 (MþNaþ).
HRMS calcd for C12H15NO2 (Mþ): 205.1103. Found
205.1111. The enantiomeric excess was determined by
chiral stationary-phase HPLC analysis (DAICEL CHIRAL-
PAK AS-H, i-PrOH/hexane 1:4, flow rate 0.6 mL/min, tR
26.0 min ((2S,3R)-isomer) and 35.5 min ((2R,3S)-isomer),
detection at 254 nm); [a]2D7¼þ12.2 (c 1.50, CHCl3, .99%
ee).
4.4.5. (2R,3S)-3-Phenethyloxirane-2-carboxlic acid tert-
butylamide (21e). Colorless oil; IR (neat) n 3312, 3063,
3026, 2968, 1667, 1537, 1496, 1479, 1455, 1364, 1223, 896,
750, 700 cm21; 1H NMR (CDCl3) d 1.33 (s, 9H), 1.81–1.89
(m, 1H), 1.99–2.06 (m, 1H), 2.73–2.84 (m, 2H), 2.93 (ddd,
J¼6.5, 4.6, 2.2 Hz, 1H), 3.14 (d, J¼2.2 Hz, 1H), 5.88 (s,
1H), 7.19–7.31 (m, 5H); 13C NMR (CDCl3) d 28.6 (£2)
31.9, 33.4, 50.9, 55.8, 59.1, 126.2, 128.3 (£2), 128.6 (£2),
140.6, 167.5; ESI-MS m/z 270 (MþNaþ). HRMS calcd for
C15H21NO2 (Mþ): 247.1572. Found 247.1576. The enantio-
meric excess was determined by chiral stationary-phase
HPLC analysis (DAICEL CHIRALPAK AS-H, i-PrOH/
hexane 1:4, flow rate 0.5 mL/min, tR 9.5 min (minor isomer)
and 13.7 min (major isomer), detection at 254 nm); [a]2D5¼
þ6.8 (c 0.78, CHCl3, 99% ee).
4.4.2. (2R,3S)-3-Phenethyloxirane-2-carboxlic acid benzyl-
amide (21b). White solid; IR (KBr) n 3262, 3054, 1654,
1
1566, 1495, 1454, 1423, 1223, 900, 719, 697 cm21; H
NMR (CDCl3) d 1.83–1.89 (m, 1H) 1.98–2.05 (m, 1H),
2.73–2.83 (m, 2H), 2.99 (ddd, J¼6.5, 4.6, 2.1 Hz, 1H), 3.30
(d, J¼2.1 Hz, 1H), 4.38 (dd, J¼14.7, 5.8 Hz, 1H), 4.42 (dd,
J¼14.7, 5.8 Hz, 1H), 6.39 (br-s, 1H), 7.05–7.37 (m, 10H);
13C NMR (CDCl3) d 31.8, 33.4, 42.8, 55.4, 59.0, 126.2,
127.6, 127.7 (£2), 128.3 (£2), 128.6 (£2), 128.7 (£2),
137.6, 140.4, 168.2; ESI-MS m/z 304 (MþNaþ). HRMS
calcd for C18H19NO2 (Mþ): 281.1416. Found 281.1421. The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALPAK AS-H,
i-PrOH/hexane 1:4, flow rate 0.8 mL/min, tR 28.4 min
((2S,3R)-isomer) and 50.5 min ((2R,3S)-isomer), detection
at 254 nm); [a]2D5¼220.1 (c 0.97, CHCl3, .99% ee).
4.4.6. (2R,3S)-3-Phenethyloxirane-2-carboxlic acid
dimethylamide (21f). Colorless oil; IR (neat) n 3480,
3025, 2930, 1652, 1496, 1455, 1398, 1264, 1154, 752,
701 cm21
;
1H NMR (CDCl3) d 1.98 (ddd, J¼7.9, 7.0,
5.8 Hz, 2H), 2.76 (dt, J¼14.0, 7.9 Hz, 1H), 2.86 (dt, J¼14.0,
7.0 Hz, 1H), 2.94 (s, 3H), 2.97 (s, 3H), 3.19 (dt, J¼2.1,
5.8 Hz, 1H), 3.32 (d, J¼2.1 Hz, 1H), 7.18–7.30 (m, 5H);
13C NMR (CDCl3) d 31.9, 33.3, 35.7, 36.2, 53.8, 57.5,
126.2, 128.4 (£2), 128.5 (£2), 140.8, 167.2; ESI-MS m/z
242 (MþNaþ). HRMS calcd for C13H17NO2 (Mþ):
219.1259. Found 219.1257. The enantiomeric excess was
determined by chiral stationary-phase HPLC analysis
(DAICEL CHIRALPAK AS-H, i-PrOH/hexane 1:4, flow
rate 0.5 mL/min, tR 42.8 min ((2S,3R)-isomer) and 51.8 min
((2R,3S)-isomer), detection at 254 nm); [a]2D6¼225.8
(c 0.97, CHCl3, 99% ee).
4.4.3. (2R,3S)-3-Phenethyloxirane-2-carboxlic acid allyl-
amide (21c). Colorless oil; IR (KBr) n 3298, 3027, 2925,
1666, 1538, 1454, 1261, 905, 700 cm21; 1H NMR (CDCl3)
d 1.83–1.90 (m, 1H), 1.98–2.06 (m, 1H), 2.73–2.83 (m,
2H), 2.97–3.01 (m, 1H), 3.27 (d, J¼2.0 Hz, 1H), 3.78–3.91
(m, 2H), 5.11–5.18 (m, 2H), 5.78 (ddd, J¼17.0, 10.0,
5.5 Hz, 1H), 6.21 (br-s, 1H), 7.17–7.23 (m, 3H), 7.30 (d,
J¼7.5 Hz, 2H); 13C NMR (CDCl3) d 31.8, 33.3, 41.0, 55.4,
59.0, 116.6, 126.2, 128.2 (£2), 128.5 (£2), 133.5, 140.4,
168.1; ESI-MS m/z 254 (MþNaþ). HRMS calcd for
C14H17NO2 (Mþ): 231.1259. Found 231.1262. The enantio-
meric excess was determined by chiral stationary-phase
HPLC analysis (DAICEL CHIRALPAK AS-H, i-PrOH/
hexane 1:4, flow rate 0.8 mL/min, tR 16.2 min (minor
isomer) and 26.4 min (major isomer), detection at 254 nm);
[a]2D6¼24.05 (c 4.2, CHCl3, 98% ee).
4.4.7. (2R,3S)-(3-Phenethyloxiranyl)-pyrrolidin-1-yl-
methanone (21g). Colorless oil; IR (neat) n 3481, 2972,
1
2875, 1650, 1455, 1415, 1341, 910, 751, 701 cm21; H
NMR (CDCl3) d 1.78–2.05 (m, 6H), 2.75 (ddd, J¼14.1, 8.3,
7.9 Hz, 1H), 2.87 (ddd, J¼14.1, 8.2, 5.8 Hz, 1H), 3.16–3.21
(m, 1H), 3.18 (d, J¼2.1 Hz, 1H), 3.23 (dt, J¼2.1, 5.7 Hz,
1H), 3.43–3.52 (m, 3H), 7.18–7.30 (m, 5H); 13C NMR
(CDCl3) d 23.8, 26.1, 32.0, 33.2,?45.6, 46.2, 54.1, 57.4,
126.1, 128.4 (£2), 128.5 (£2), 140.8, 165.8; ESI-MS m/z
268 (MþNaþ). HRMS calcd for C15H19NO2 (Mþ):
245.1416. Found 245.1415. The enantiomeric excess was
determined by chiral stationary-phase HPLC analysis
(DAICEL CHIRALPAK AS-H, i-PrOH/hexane 1:1, flow
rate 0.5 mL/min, tR 30.9 min (minor isomer) and 43.5 min
(major isomer), detection at 254 nm); [a]2D6¼232.1 (c 0.77,
CHCl3, .99% ee).
4.4.4. (2R,3S)-3-Phenethyloxirane-2-carboxlic acid cyclo-
hexylamide (21d). White solid; IR (KBr) n 3295, 3063,
3027, 2930, 2850, 1653, 1540, 1497, 1450, 1314, 1123,
1
1105, 899, 739, 695 cm21; H NMR (CDCl3) d 1.07–1.19
(m, 3H), 1.31–1.38 (m, 2H), 1.58–1.72 (m, 2H), 1.79–1.91
(m, 2H), 1.98–2.04 (m, 1H), 2.73–2.83 (m, 2H), 2.94 (ddd,
J¼6.5, 4.6, 2.2 Hz, 1H), 3.23 (d, J¼2.2 Hz, 1H), 3.69–3.76
(m, 1H), 5.95 (d, J¼7.0 Hz, 1H), 7.18–7.31 (m, 5H); 13C
NMR (CDCl3) d 24.7 (£2) 25.4, 31.8, 32.9, 33.0, 33.4, 47.6,
4.4.8. (2R,3S)-3-(4-Phenylbutyl)-oxirane-2-carboxlic
acid methylamide (21h). White solid; IR (neat) n 3277,
3107, 3026, 2936, 2853, 1662, 1567, 1451, 1412, 1268,
1
1162, 893, 749, 697 cm21; H NMR (CDCl3) d 1.48–1.74

10496
T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
(m, 6H), 2.62 (t, J¼7.3 Hz, 2H), 2.79 (d, J¼5.2 Hz, 3H),
2.92 (dt, J¼6.0, 2.1 Hz, 1H), 3.22 (d, J¼2.1 Hz, 1H), 6.11
(br-s, 1H), 7.15–7.18 (m, 3H), 7.23–7.29 (m, 2H); 13C
NMR (CDCl3) d 25.2, 25.4, 31.0, 31.6, 35.7, 55.4, 59.6,
125.8, 128.3 (£2), 128.4 (£2), 142.1, 169.2; ESI-MS m/z
256 (MþNaþ). HRMS calcd for C14H19NO2 (Mþ):
233.1416. Found 233.1415. The enantiomeric excess was
determined by chiral stationary-phase HPLC analysis
(DAICEL CHIRALPAK AS-H, i-PrOH/hexane 1:4, flow
rate 1.0 mL/min, tR 13.5 min (minor isomer) and 24.7 min
(major isomer), detection at 254 nm); [a]2D5¼þ21.8 (c 1.29,
CHCl3, .99% ee).
analysis (DAICEL CHIRALPAK AS-H, i-PrOH/hexane
1:4, flow rate 1.0 mL/min, tR 17.4 min ((2S,3R)-isomer) and
31.1 min ((2R,3S)-isomer), detection at 254 nm); [a]2D6¼
250.8 (c 0.76, CHCl3, .99% ee).
4.5.2. (2R,3S)-3-Phenyloxirane-2-carboxlic acid benzyl-
amide (21l).9 The enantiomeric excess was determined
by chiral stationary-phase HPLC analysis (DAICEL
CHIRALPAK AS-H, i-PrOH/hexane 1:4, flow rate 1.0 mL/
min, tR 25.0 min ((2S,3R)-isomer) and 62.2 min ((2R,3S)-
isomer), detection at 254 nm); [a]2D5¼286.1 (c 0.62, CHCl3,
.99% ee).
4.4.9. (2R,3S)-3-Propyloxirane-2-carboxlic acid benzyl-
amide (22i). White solid; IR (KBr) n 3223, 3065, 2954,
4.5.3. (2R,3S)-3-Phenyloxirane-2-carboxlic acid dimethyl-
amide (21m).30 The enantiomeric excess was determined
by chiral stationary-phase HPLC analysis (DAICEL
CHIRALPAK AS-H, i-PrOH/hexane 1:1, flow rate 0.5 mL/
min, tR 23.3 min (minor isomer) and 28.5 min (major
isomer), detection at 254 nm); [a]2D6¼2109.4 (c 1.09,
CHCl3, .99% ee).
1
1654, 1560, 1451, 1257, 1030, 907, 696 cm21; H NMR
(CDCl3) d 0.97 (t, J¼7.1 Hz, 3H), 1.47–1.66 (m, 4H), 2.95
(m, 1H), 3.27 (d, J¼2.1 Hz, 1H), 4.42 (d, J¼6.1 Hz, 2H),
5.80 (s, 1H), 7.26–7.35 (m, 5H); 13C NMR (CDCl3) d 13.7,
19.0, 33.7, 42.8, 55.4, 59.6, 127.6, 127.7 (£2), 128.8 (£2),
137.6, 168.5; ESI-MS m/z 242 (MþNaþ). HRMS calcd
for C13H17NO2 (Mþ): 219.1259. Found 219.1264. The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALPAK AS-H,
i-PrOH/hexane 1:4, flow rate 0.5 mL/min, tR 26.3 min
(minor isomer) and 41.5 min (major isomer), detection at
254 nm); [a]2D2¼21.78 (c 0.56, CHCl3, 94% ee).
4.5.4. (2R,3S)-3-(4-Flurophenyl)-oxirane-2-carboxlic
acid methylamide (21n). White solid; IR (KBr) n 3300,
3121, 1652, 1578, 1509, 1413, 1219, 1155, 887, 841, 554,
528 cm21; 1H NMR (CDCl3) d 2.87 (d, J¼5.2 Hz, 3H), 3.50
(d, J¼2.1 Hz, 1H), 3.86 (d, J¼2.1 Hz, 1H), 6.25 (br-s, 1H),
7.04–7.07 (m, 2H), 7.23–7.27 (m, 2H); 13C NMR (CDCl3)
d 25.6, 58.5, 58.9, 115.7 (d, J¼21.6 Hz) (£2), 127.5
(d, J¼9.3 Hz) (£2), 130.72 (d, J¼3.1 Hz), 163.1 (d, J¼
248 Hz), 167.8; ESI-MS m/z 218 (MþNaþ). HRMS calcd
for C10H10FNO2 (Mþ): 195.0696. Found 195.0704. The
enantiomeric excess was determined by chiral stationary-
phase HPLC analysis (DAICEL CHIRALPAK AS-H,
i-PrOH/hexane 1:4, flow rate 1.0 mL/min, tR 20.5 min
(minor isomer) and 40.0 min (major isomer), detection at
254 nm); [a]2D6¼þ39.7 (c 0.64, CHCl3, 99% ee).
4.4.10. (2R,3S)-3-Cyclohexyloxirane-2-carboxlic acid
benzylamide (20j).28 The enantiomeric excess was deter-
mined by chiral stationary-phase HPLC analysis (DAICEL
CHIRALPAK AS-H, i-PrOH/hexane 1:4, flow rate 0.5 mL/
min, tR 27.6 min ((2R,3S)-isomer) and 68.0 min ((2S,3R)-
isomer), detection at 254 nm); [a]2D7¼24.14 (c 0.29, CHCl3,
.99% ee).
4.5. General procedure for the catalytic asymmetric
epoxidation of b-aryl type a,b-unsaturated amides
(condition B)
4.5.5. (2R,3S)-3-p-Tolyloxirane-2-carboxlic acid methyl-
amide (21o). White solid; 1H NMR (CDCl3) d 2.34 (s, 3H),
2.85 (d, J¼5.0 Hz, 3H), 3.52 (d, J¼2.0 Hz, 1H), 3.83 (d,
J¼2.0 Hz, 1H), 6.34 (s, 1H), 7.12–7.16 (m, 4H); 13C NMR
(CDCl3) d 21.2, 25.5, 58.9, 59.1, 125.7 (£2), 129.2 (£2),
131.8, 138.9, 168.2; ESI-MS m/z 214 (MþNaþ). HRMS
calcd for C11H13NO2 (Mþ): 191.0946. Found 191.0940. The
enantiomeric excess of 3o was determined by chiral
stationary-phase HPLC analysis (DAICEL CHIRALPAK
AS-H, i-PrOH/hexane 1:4, flow rate 1.0 mL/min, tR
18.7 min (minor isomer) and 37.9 min (major isomer),
detection at 254 nm); [a]2D7¼253.4 (c 1.31, CHCl3, .99%
ee).
A THF solution (2.5 mL) of (S)-BINOL (7.2 mg,
0.025 mmol) and triphenylarsine oxide (8.1 mg,
0.025 mmol) was added to a stirred dry MS 4A (250 mg,
dried for 3 h at 1808C under reduced pressure), then Sm(O-i-
Pr)3 (0.25 mL, 0.025 mmol, 0.1 M solution in THF) was
added to the reaction mixture at room temperature. After
stirring for 45 min at the same temperature, TBHP
(0.077 mL, 0.6 mmol, 3.9 M solution in toluene) was
added. After stirring for 10 min, 20k (40.3 mg, 0.25 mmol)
was added directly and the mixture was stirred at room
temperature. After complete consumption of the starting
material (18 h), the reaction mixture was diluted with ethyl
acetate (10 mL) and quenched with 2% citric acid (2.5 mL).
The water layer was extracted with ethyl acetate (10 mL),
and the combined organic layers were washed with brine
(5 mL) and dried over Na2SO4. After concentration in
vacuo, the residue was purified by flash chromatography
(SiO2, hexane/ethyl acetate¼4:1–3:1) to give epoxy amide
21k (42.3 mg, 95%) as a white yellow solid.
4.5.6. The absolute configurations of 21. The absolute
configurations of 21k29 and 21l9 were determined by
comparing between measured and reported optical
rotations. The absolute configurations of 21a, 21b, 21f,
and 21j were determined by comparing the measured optical
rotations with authentic samples.31
Acknowledgements
4.5.1. (2R,3S)-3-Phenyloxirane-2-carboxlic acid methyl-
amide (21k).29 White yellow solid. The enantiomeric
excess was determined by chiral stationary-phase HPLC
This work was supported by CREST, The Japan Science and
Technology Corporation (JST), RFTF of Japan Society for

T. Ohshima et al. / Tetrahedron 59 (2003) 10485–10497
10497
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Calculations were
performed with the Gaussian 98 program package; Revision
A.7, Gaussian, Inc., Pittsburgh PA, 1998.
the Promotion of Science (JSPS), and fellowship from JSPS
(to T. N.).
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