Asymmetric epoxidation of cinnamic acid derivatives by in situ generated dioxiranes of chloroacetones: Scope and limitations

Article abstract of DOI:10.1016/j.tetasy.2010.07.012

Efficient epoxidation of chiral cinnamic acid derivatives has been achieved by in situ generated dioxiranes of chloroacetones with moderate to good diastereoselectivity (dr up to 90:10) in high yields. Reactivity of cinnamic acid derivatives containing different chiral auxiliaries versus chloroacetones-monochloroacetone 3 (MCA), 1,1-dichloroacetone 4 (DCA) and 1,1,1-trichloroacetone 5 (TCA) and Oxone loading was studied. Both Oxone loading and reaction time reduce with an increase of chlorine atoms in the acetone. The use of 1.1 equiv of TCA was found to be effective for the epoxidation of cinnamate substrates and enhances the reaction up to 4-10-fold compared to acetone and that also decreases the Oxone loading. This method provided methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for the synthesis of diltiazem hydrochloride, with >99% of enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2010.07.012

Tetrahedron: Asymmetry 21 (2010) 2223–2229
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Tetrahedron: Asymmetry
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Asymmetric epoxidation of cinnamic acid derivatives by in situ generated
dioxiranes of chloroacetones: scope and limitations
*
Saumen Hajra , Manishabrata Bhowmick
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient epoxidation of chiral cinnamic acid derivatives has been achieved by in situ generated dioxir-
anes of chloroacetones with moderate to good diastereoselectivity (dr up to 90:10) in high yields. Reac-
tivity of cinnamic acid derivatives containing different chiral auxiliaries versus chloroacetones–
monochloroacetone 3 (MCA), 1,1-dichloroacetone 4 (DCA) and 1,1,1-trichloroacetone 5 (TCA) and
Oxone™ loading was studied. Both Oxone™ loading and reaction time reduce with an increase of chlorine
atoms in the acetone. The use of 1.1 equiv of TCA was found to be effective for the epoxidation of cinna-
mate substrates and enhances the reaction up to 4–10-fold compared to acetone and that also decreases
the Oxone™ loading. This method provided methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (ꢀ)-2, a key
intermediate for the synthesis of diltiazem hydrochloride, with >99% of enantiomeric purity.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 16 June 2010
Accepted 13 July 2010
Available online 10 August 2010
1. Introduction
and Oxone™ (4–11 equiv). This might be due to the low boiling
point (22 °C) and high volatility of 1,1,1-trifluoroacetone. This
a
,b-Epoxy carbonyls are key building blocks in organic synthe-
prompted us to consider that cheaper and easily synthesizable
chloroacetones could be an alternative to fluoroacetones. As elec-
tronegativity of chlorine is close to flurorine, dioxirane of chloroac-
etones might have similar reactivity. More important, the high
boiling point of chloroacetones might reduce the ketone as well
as Oxone™ loadings.
sis, as these versatile functionalities are readily and stereoselective-
ly transformed by ring opening into a variety of oxyfunctionalized
compounds.1 The development of an efficient stereocontrolled
method for the synthesis of chiral
considerable interest. Though much progress has been made, the
a,b-epoxy carbonyls is still of
asymmetric epoxidation of allylic alcohols and olefins, chiral auxil-
We are interested in the asymmetric epoxidation of chiral
cinnamic acid derivatives because chiral epoxy cinnamoyl com-
pounds are important building blocks for the synthesis of many
biologically active compounds for example, methyl (2R,3S)-3-(4-
methoxyphenyl)glycidate (ꢀ)-2, a key intermediate for the synthe-
sis of diltiazem hydrochloride 1 that is one of the most potent
calcium antagonists and has been used as a drug for the treatment
of angina and hypertension (Fig. 1). Thus, we report an efficient
iary based asymmetric epoxidation of a,b-unsaturated acid deriva-
tives is also an important strategy in organic synthesis. Peracids2
and dioxiranes3 such as dimethyl dioxirane (DMD) are the popular
oxidizing agents for the epoxidaton of alkenes. Adam et al. reported
the opposite
p-face selective epoxidation of chiral tiglic amides
using dimethyl dioxirane (DMD) and m-chloroperbenzoic acid
(m-CPBA).4 To avoid preparation and storing of DMD,5 it is more
convenient to epoxidize the alkenes by in situ generated dioxirane.
As dioxiranes are electrophilic in nature, epoxidation of electron-
deficient alkenes using in situ generated dioxiranes is usually very
slow, when normal ketones such as acetone,6 2-butanone6 and
hexanones6 are used. Yang et al.7 described the enhanced rate of
epoxidation by in situ generated methyl(trifluoromethyl) dioxirane
from 1,1,1-trifluoroacetone and Oxone™, where the high electro-
negativity of fluorine makes it a stronger epoxidizing agent. Later
Chen et al. demonstrated8 the asymmetric epoxidation of various
camphor derived N- and O-enones by in situ generated dioxirane
using a large excess of the costly trifluoroacetone (33–47 equiv)
OMe
O
S
O
OAc
MeO
N
OMe
O
(2R,3S)-(-)-2
1
NMe2 .HCl
* Corresponding author. Tel.: +91 3222 283340.
E-mail address: shajra@chem.iitkgp.ernet.in (S. Hajra).
Figure 1.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.012

2224
S. Hajra, M. Bhowmick / Tetrahedron: Asymmetry 21 (2010) 2223–2229
Table 1
epoxidation of cinnamic acid derivatives containing different chiral
auxiliaries by in situ generated dioxiranes using 1.1 equiv of 1,1,1-
trichloroacetone 5 (Fig. 2) and Oxone™ (1.5–5.0 equiv) that pro-
vides moderate to good diastereoselectivities (up to 90:10) in high
yields and the study on the reactivity of in situ generated dioxir-
anes of different chloroacetones 3–5 towardchiral cinnamic acid
derivatives versus Oxone™ loading.
Epoxidation of 4 in the presence of different chloroacetones
O
O
ketone,
O
oxoneTM, NaHCO3
R1
R2
R1
R2
CH3CN/H2O, 25 °C
7
6a: R1 = 4-MeOC6H4, R2 =OMe
6b: R1 = Ph, R2 = OMe
6c: R1 = Ph, R2 = Ph
6d: R1 = 4-MeOC6H4, R2 = Ph
6e: R1 = Me, R2 = OMe
6f: R1, R2 = -(CH2)3-
O
O
O
Cl
Cl
t (h) Conv.a Yielda
Cl
Cl
Cl
Entry Substrate Ketone
Oxone™ Base
(equiv) (equiv)
Me
Me
Me
(%)
(%)
Cl
1
2
3
4
5
6
6a
6a
6a
6a
6a
6a
Acetone 1.5
3.5
3.5
3.5
4.5
3.5
3.0
3
3
3
2
45
67
95
—
3
4
4
5
5
1.5
1.5
2.0
1.5
1.2
55
81
90
85
90
3
4
5
100
Figure 2.
0.8 100
0.8 100
7
8
9
10
11
6b
6b
6b
6b
6b
Acetone 1.5
3.5
3.5
3.5
3.5
8.5
15
28
30
41
68
100
28
30
41
68
2. Results and discussion
3
4
5
5
1.5
1.5
1.5
3.5
15
15
15
9
To outline suitable reaction conditions, initially the epoxidation
of achiral cinnamoyl substrates 6 was studied under different con-
ditions. Initially 50% aqueous acetonitrile was found to be an effec-
tive solvent, as either lower or higher percentages of water retard
the reaction. When a solution of methyl 4-methoxycinnamate 6a
in 50% aqueous acetonitrile and acetone (water/acetonitrile/ace-
tone 2:1:1) was reacted with 1.5 equiv of Oxone™, where acetone
functions as a ketone source as well as co-solvent, it showed 45%
conversion after 3 h (Table 1; entry 1). Epoxidation of 6a with
1.1 equiv of monochloroacetone 3 (MCA) and dichloroacetone 4
(DCA) under similar conditions provided very good conversion of
67% and 95% after 3 h, respectively (entries 2 and 3); compared
to the reaction with acetone (entry 1). DCA mediated epoxidation
could even attend 100% conversion, within 2 h, when a small ex-
cess of Oxone™ (2.0 equiv) was used (entry 4). As presumed, the
reactivity of oxirane further increases in the case of 1,1,1-trichloro-
acetone 5 (TCA) and showed 100% conversion within 1 h (entry 5).
Even 1.2 equiv of Oxone™ loading was found to be sufficient for
TCA (entry 6). There was no appreciable change in the rate and
conversion of the reaction with higher equivalents of DCA and
TCA. Thus, 1.1 equiv of chloroacetones were found to be optimum
>99 (92)
12
13
14
15
16
6c
6c
6c
6c
6c
Acetone 1.5
3.5
3.5
3.5
3.5
9.5
15
15
15
1.5 100
0.5 100
46
50
60
46
50
60
>99 (93)
>99
3
4
5
5
1.5
1.5
1.5
4.0
17
18
19
20
21
22
23
6d
6d
6d
6d
6d
6e
6f
Acetone 1.5
3.5
3.5
3.5
3.5
3.0
3
3
2
75
85
100
70
75
90
90
3
1.5
3
2.0
4
1.5
0.7 100
0.2 100
5
1.2
>99 (93)
3/4/5
3/4/5
1.5–4
1.5–4
3.5–10 12
3.5–10 12
No reaction
No reaction
Determined by 1H NMR analysis of the crude reaction mixture with succinimide
as an internal standard. Yields in the parentheses refer to the isolated yields after
column chromatography.
a
(entry 19). So, it was observed that both Oxone™ loading and reac-
tion time decrease with the increase of chlorine atom in the ace-
tone. However, under the same reaction conditions, methyl
crotonate 6e and cyclohexenone 6f did not show any reaction even
upon use of a large excess of Oxone™ (entries 22 and 23). It might
be concluded that in situ generated methyl(trichloromethyl)dioxi-
rane is not sufficiently reactive toward more electron-deficient al-
kenes such as crotonate and cyclohexenone.
for this epoxidation reaction. The reactivity of other
a,b-unsatu-
rated carbonyls such as ester 6b and chalcones 6c and 6d (Table 1)
were also studied. Unsubstituted methyl cinnamate 6b is more
electron-deficient than 6a; so it is expected to be less reactive to-
ward in situ generated dioxirane. It provided only 28% conversion
with acetone and 30% for MCA after 15 h (entries 7 and 8) and DCA
mediated epoxidation of 6b showed little improvement (entry 9).
Epoxidation of 6b with TCA and 1.5 equiv of Oxone™ could not
achieve 100% conversion even after 15 h (entry 10) and that re-
quired excess of Oxone™ (3.5 equiv; entry 11). A similar trend
was also observed for chalcone 6c (entries 12–16) and it was found
to be more reactive than the corresponding ester 6b. TCA mediated
epoxidation of 6c led to 100% conversion after 1.5 h (entry 15) and
the reaction time further decreased to 0.5 h, when 4.0 equiv of
Oxone™ was used (entry 16). It seems the electron-donating reso-
nance (+R) effect of a phenyl group in chalcone 6c reduces the elec-
tron-withdrawing effect of the carbonyl group and in turn
increases the reactivity toward electrophilic dioxirane. Similarly
electron rich chalcone, 3-(4-methoxyphenyl)-1-phenylpropenone
6d showed a similar trend as of 4-methoxy cinnamate 6a and with
better reactivity. It showed 75% conversion with acetone after 3 h
(entry 17), and under the similar reaction conditions TCA showed
100% conversion within 15 min (entry 21) and DCA mediated reac-
tion took 45 min (entry 20). A similar conversion could also be
achieved by MCA after 2 h when 2.0 equiv of Oxone™ was used
Toward the development of an asymmetric epoxidation and to
study the reactivity of the substrates along with diastereoselectiv-
ity, we carried out the epoxidation of
a,b-unsaturated carboxylic
acid derivatives containing different chiral auxiliaries such as
Evans oxazolidinone (Table 2), oxazolidine, (Table 3) and Oppol-
zer’s sultam (Table 4). We initially studied the epoxidation of chiral
(4S)-N-(p-methoxycinnamoyl)-4-(1-methyl)-2-oxazolidinone 8a
(Table 2). As MCA mediated epoxidation showed a poor to moder-
ate increase in reactivity, epoxidation of chiral cinnamoyl sub-
strates with MCA was not included. However, epoxidation in the
presence of acetone as a ketone source as well as co-solvent was
studied in order to compare the reactivity with DCA and TCA.
Epoxidation of 8a with 1.5 equiv of Oxone™ in CH3COCH3/
CH3CN/H2O (1:1:2) gave 65% conversion with a diastereomeric ra-
tio (dr) of 55:45 (entry 1) after 10 h. The same reaction showed
100% conversion within half an hour, when TCA 5 (1.1 equiv) and
Oxone™ (1.5 equiv) were used (entry 3) and for DCA 4 it took 1 h
(entry 2). Also 0.5 equiv of TCA was also found to be effective for
the 100% epoxidation of 8a (entry 4). We also studied the epoxida-
tion of other N-enoyl-2-oxazolidinone substrates (Table 2). Epoxi-

S. Hajra, M. Bhowmick / Tetrahedron: Asymmetry 21 (2010) 2223–2229
2225
Table 2
Epoxidation of 8 in the presence of chloroacetones
O
O
O
ketone
O
oxoneTM, NaHCO3
R
N
R
N
CH3CN/H2O, 25 °C
9
O
O
O
8a: R = 4-MeOC6H4, 8b: R = Ph, 8c: R = 4-ClC6H4, 8d: R = Me
Entry
Substrate
Ketone
Oxone™ (equiv)
Base (equiv)
t (h)
dra
Conv.a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
8a
8a
8a
8a
8b
8b
8b
8b
8b
8c
8c
8c
8c
8c
8d
Acetone
4
1.5
1.5
1.5
1.5
1.5
1.5
4.0
1.5
2.5
1.5
1.5
3.5
1.5
3.0
1.5–4
3.5
3.5
3.5
3.5
3.5
3.5
10
10
1
55:45
56:44
57:43
56:44
ND
ND
56:44
ND
55:45
ND
ND
65:35
63:37
62:38
No reaction
65
100
100 (90)
100
35
5
0.5
0.5
10
10
10
10
4
6
6
6
6
5b
Acetone
4
4
5
65
100 (93)
3.5
6.0
80c
5
100
20
55
Acetone
4
4
5
5
4/5
3.5
3.5
8.5
3.5
7.0
80 (75)
85c
6
12
94c
3.5–10
a
b
c
Determined by 1H NMR analysis of the crude reaction mixture with succinimide as an internal standard.
Using 0.5 equiv of TCA.
10–15% epoxide decomposition compounds. Isolated yields after column chromatography are referred in the parentheses. ND: Not determined.
Table 3
Epoxidation of 10 in the presence of chloroacetones
O
O
ketone
O
oxoneTM, NaHCO3
Ph
N
Ph
N
O
O
CH3CN/H2O, 25 °C
10
11
Entry
Ketone
Oxone™
Base (equiv)
t (h)
dra
Conv.a (%)
1
2
3
4
Acetone
2.5
2.5
1.5
2.5
6.0
6.0
3.5
6.0
12
5
6
ND
35
4
5
5
87:13
88:12
90:10
89b
88b
100 (95)
2
a
Determined by 1H NMR analysis of the crude reaction mixture with succinimide as an internal standard.
Along with 10–24% epoxide decomposition products. Isolated yield after column chromatography is referred in the parenthesis. ND: Not determined.
b
dation of 8b with 1.5 equiv of Oxone™ and acetone as a ketone
gave only 35% conversion after 10 h (entry 5), and DCA showed
65% conversion (entry 6). Under the same reaction condition, TCA
gave 80% conversion along with 15% of undesired compounds
(entry 8). When the reaction was carried out with an excess of
Oxone™ and NaHCO3 in portions, it provided an improved conver-
sion (entries 7 and 9). DCA mediated epoxidation of 8b using
4.0 equiv of Oxone™, NaHCO3 (10 equiv) afforded 100% conversion
after 10 h (entry 7), and for TCA 5, 2.5 equiv of Oxone™ and 4 h
was found to be sufficient (entry 9). Epoxidation of cinnamoyl
substrate 8c with different acetones was also studied. Among
these, DCA was found to be a more efficient ketone source, which
gave a clean epoxidation with 80% conversion and moderate
diastereoselectivity (65:35; entry 12). TCA also showed good con-
version (94%) along with the formation of 15% epoxide decomposi-
tion compounds (entry 14). Acetone showed only 20% conversion
(entry 10). Similar to methyl crotonate, alkenoyl substrate 8d
did not respond to this epoxidation under different reaction condi-
tions (entry 15). Thus, epoxidation of cinnamoyl substrates
containing an Evans oxazolidinone chiral auxiliary by the in situ
generated dioxiranes of acetone/chloroacetones showed poor to
moderate diastereoselectivity and the rate enhanced on increasing
the chlorine atom in acetone that also lowered the Oxone™-
loading.
Again, asymmetric epoxidation of N-cinnamoyl oxazolidine 10
was performed under similar conditions. It was observed that the
reaction of 10 with 2.5 equiv of Oxone™ gave only 35% of conver-
sion after 12 h when acetone was used as a ketone source (Table 3,
entry 1). Under the similar reaction condition that is, use of
2.5 equiv of Oxone™, DCA 4 (1.1 equiv) mediated epoxidation of
10 provided improved conversions; however the formation of an
appreciable amount of by-products was an additional problem
(entry 2). Shorter reaction time (3 h) using TCA 5 (1.1 equiv) as a
ketone afforded a clean reaction with 100% conversion and good
diastereoselectivity (90:10) (entry 4). It was found that under
similar reaction conditions cinnamoyl substrate 10 containing oxa-
zolidine chiral auxiliary underwent faster reaction with high dia-
stereoselectivity (Table 3; entry 4) compared to the substrate 8b
containing oxazolidinone chiral auxiliary (Table 2; entries 8 and
9). It is to be noted that N-(4-methoxycinnamoyl) oxazolidine

2226
S. Hajra, M. Bhowmick / Tetrahedron: Asymmetry 21 (2010) 2223–2229
Table 4
Epoxidation of 12 in the presence of chloroacetones
ketone
O
O
oxoneTM, NaHCO3
O
N
Ar
N
Ar
CH3CN/H2O, 25 °C
S
S
O
O
O
O
13
12
12a: Ar = 4-MeOC6H4, 12b: Ar = Ph
Entry
Substrate
Ketone
Oxone™ (equiv)
Base (equiv)
t (h)
dra
Conv.a (%)
1
2
3
4
5
6
7
8
9
12a
12a
12a
12a
12a
12a
12b
12b
12b
12b
12b
12b
Acetone
4
4
5
5
5
Acetone
Acetone
4
4
5
5
1.5
1.5
2.5
1.5
2.5
2.5
1.5
5.0
1.5
5.0
1.5
5.0
3.5
3.5
6.0
3.5
4.7
11
3.5
12
3.5
12
3.5
12
4
3
3
2
2
ND
ND
85:15
ND
ND
84:16
ND
ND
ND
ND
20
54
82
85b
100b
100c (92)
<10
18
2
12
12
12
12
12
12
27
30
36
55 (51)
10
11
12
ND
82:18
a
b
c
Determined by 1H NMR analysis of the crude reaction mixture with succinimide as an internal standard.
Along with 18–20% epoxide decomposition products.
Along with 8% epoxide decomposition products. Isolated yields after column chromatography are referred in the parentheses. ND: Not determined.
could not be prepared in pure form, because it decomposed on sil-
ica gel.
with cinnamoyl substrates 12 containing a sultam chiral auxiliary,
which are less reactive towardelectrophilic dioxiranes compared
to the substrates 8 and 10 containing oxazolidinone and oxazolidine
chiral auxiliaries, respectively. However, substrates 12 were found
to provide better selectivity than the oxazolidinone substrates 8. It
is to be noted that the solubility of compounds 12 in 50% aqueous
CH3CN was poor; that might be an additional reason for the low con-
version. Stereochemistry of the major epoxide 13 was assigned by
comparison with the literature data of epoxide 13b.8a
Similar to the substrates 8 and 10, the rate of epoxidation of 12
containing camphorsultam chiral auxiliary also enhanced on
increasing the chlorine atoms in the acetone and with lower rates.
The sultam chiral auxiliary showed good diastereoselectivity
(Table 4). Epoxidation of electron-rich substrate 12a could not
achieve 100% conversion with acetone, and DCA 4 even using excess
Oxone™ (entries 1–3). Moreover, 100% conversion with good dia-
stereoselectivity (dr: 84/16) could only be achieved with 2.5 equiv
of Oxone™ by TCA 5 (entry 5). TCA-mediated reactions produced
20% of undesired epoxide decomposition compounds, which could
be minimized by using an excess of NaHCO3 (11 equiv) (entry 6).
However, oxazolidinone substrate 8a showed 100% conversion
within half an hour with only 1.5 equiv of Oxone™ (Table 2, entries
3 and 4). Similarly substrate 12b provided moderate conversion
(55%) and good diastereoselectivity (82:18) when an excess of
Oxone™ (5 equiv) was used (entry 12). This might be due to the
presence of a strong electron-withdrawing sulfonyl group (–SO2–)
The configurational assignment of the major epoxides 9 was
confirmed by confirming the stereochemistry of 9a (Scheme 1).
The reaction of the non-separable mixture of diastereomers 9a
was reacted with MeOLi, prepared by reaction of n-BuLi and MeOH
at ꢀ78 °C and produced (+)-methyl-3-(4-methoxyphenyl)glycidate
(+)-2. The specific rotation of (+)-methyl glycidates (+)-2
{½a 2D9
¼ þ51:5 (c 0.5, MeOH) was compared with the literature data
ꢁ
{lit. ½a 2D4
ꢁ
¼ ꢀ205 (c 1.0, MeOH)}.9 This ascertained the stereochem-
istry of major epoxide 9. Similarly pure 13a, obtained after recrys-
tallization from 30% ethyl acetate in hexane, was reacted with
O
O
O
O
OMe
N
MeOH, n-BuLi
-78 oC, 10 min,
55%
(+)-2
O
MeO
MeO
O
9a
[α]D28 = +51.5 (c 0.5, MeOH)
O
O
O
O
MeOH, n-BuLi
N
MeO
-78 oC, 10 min,
S
O
OMe
79%
OMe
[α]D29 = -209.5 (c 1.0, MeOH)
O
(-)-2
13a
Lit: [α]D24 = -205 (c 1.0, MeOH)
Scheme 1. Configurational assignments of epoxides 9 and 13 and the synthesis of (ꢀ)-methyl glycidate (ꢀ)-2.

S. Hajra, M. Bhowmick / Tetrahedron: Asymmetry 21 (2010) 2223–2229
2227
MeOLi at ꢀ78 °C and produced (ꢀ)-methyl-3-(4-methoxyphenyl)-
namic acid derivatives by in situ generated dioxiranes using
1.1 equiv of chloroacetones and 1.5–5.0 equiv of Oxone™. As the
number of chlorine atom increases in the acetone, the rate of epox-
idation enhances and decreases the Oxone™ loading. Thus DCA 4
and TCA 5 were found to be efficient alternate ketones for the
epoxidation of cinnamyl substrates. These enhanced the reaction
up to 4–10-fold compared to acetone and also decreased the
Oxone™ loading. A chiral auxiliary also plays an important role
on reactivity and selectivity for the epoxidation by in situ gener-
ated dioxiranes. Cinnamoyl substrates containing an oxazolidinone
chiral auxiliary smoothly underwent asymmetric epoxidation with
moderate diastereoselectivity (up to 65:35) and substrates con-
taining sultam chiral auxiliary underwent epoxidation slowly,
but with good diastereoselectivity (up to 85:15). The reactivity of
cinnamic acid derivatives decreases from the substrate containing
oxazolidine to oxazolidinone and sultam chiral auxiliaries. This
method could produce (ꢀ)-methyl-3-(4-methoxyphenyl)glycidate
(ꢀ)-2 with >99% of enantiomeric purity.
glycidate (ꢀ)-2 with specific rotation of ½a D29
¼ ꢀ209:5, (c 1.0,
ꢁ
MeOH) {lit. ½a 2D4
ꢁ
¼ ꢀ205 (c 1.0, MeOH)}.9 Thus it provided enanti-
omerically pure (>99% ee) (ꢀ)-methyl glycidate (ꢀ)-2, the key
intermediate for the synthesis of many biologically active
compounds, in particular, diltiazem 1. The formation of glycidate
(ꢀ)-2 from epoxide 13a further supports the stereochemistry of
epoxide 13. The configurational assignment of 11 was confirmed
from single crystal X-ray analysis (Fig. 3).10
4. Experimental
4.1. General methods
All reactions were conducted with oven-dried glassware under
an atmosphere of argon. Commercial grade reagents were used
without further purification. Solvents were dried and distilled fol-
lowing usual protocols. Flash chromatography was carried out
using Rankem Silica-gel (230–400 mesh) purchased from Ranbaxy,
India. TLC was performed on aluminum-backed plates coated with
Silica Gel 60 with F254 indicator (Merck).
Figure 3. ORTEP diagram of compound 11 with thermal ellipsoid at 30% probability
level.
Among the chiral auxiliaries, the sultam was found to provide
better diastereoselectivity by in situ generated dixiranes of chloro-
The 1H NMR spectra were measured on a Bruker-200 (200 MHz)
and Bruker-400 (400 MHz) using CDCl3 as a solvent. 13C NMR spec-
tra were measured with Bruker-200 (50 MHz) and Bruker-400
(100 MHz) using CDCl3 as a solvent. 1H NMR chemical shifts are
expressed in parts per million (d) downfield to CHCl3 (d = 7.26);
13C NMR chemical shifts are expressed in parts per million (d)
relative to the central CDCl3 resonance (d = 77.0). Coupling con-
stants in 1H NMR are expressed in Hertz. Specific optical rotations
were measured with JASCO P-1020 Polarimeter. IR spectra were
recorded using Perkin–Elmer Spectrum RꢂI FTIR Spectrometer.
Elemental analyzes were carried out on a Perkin–Elmer 2400-II.
Melting points were measured using Toshniwal (India) melting
point apparatus.
acetones. It is known in the literature that for
a-unsubstituted
camphorsultam N-enones, the s-cis conformation 12 is energeti-
cally favoured over s-trans 120 where the carbonyl group is ori-
ented away from the sulfonyl moiety to avoid dipole–dipole
interaction.11 Thus, an attack of methyl(trichloromethyl)dioxirane
from the top Re face of s-cis conformation of N-cinnamoyl cam-
phorsultam 12 provides the desired major epoxide 13 (Scheme 2).
3. Conclusions
In conclusion, we have developed an efficient epoxidation of
cinnamates and chalcones, in particular chiral
a,b-unsaturated cin-
O
O
CCl3
Me
Re face
O
O
N
N
Ar
S
S
Ar
O
O
O
O
12
12´
O
O
N
Ar
S
O
O
13
Scheme 2. Proposed mechanism for the epoxidation of 12.

2228
S. Hajra, M. Bhowmick / Tetrahedron: Asymmetry 21 (2010) 2223–2229
4.2. General procedure for epoxidation
4.2.3. (4S,20S,30R) and (4S,20R,30S)-3-[30-(4-Chlorophenyl)-
oxiranecarbonyl]-4-(1-methylethyl)-2-oxazolidinone 9c
Epoxidation with acetone. To a stirred solution (0.03 M) of sub-
strate in acetone/acetonitrile/water (1:1:2) were added Oxone™
and NaHCO3 in portions at rt. The reaction was monitored by TLC
and the resulting suspension was treated with water. The reaction
mixture was extracted with Et2O, washed with brine, dried over
anhydrous Na2SO4, and evaporated to give the crude epoxide. Flash
chromatography over silica-gel column gave pure epoxide.
Epoxidation with chloroacetones. Chloroacetone was added to a
stirred solution (0.03 M) of substrate in 50% aqueous acetonitrile.
A homogeneous mixture of Oxone™ and NaHCO3 was added to
the reaction mixture in portions. The reaction was monitored by
TLC and the resulting suspension was treated with water. The reac-
tion mixture was extracted with Et2O, washed with brine, dried
over anhydrous Na2SO4 ,and evaporated to give the crude epoxide.
Flash chromatography over a silica-gel column afforded pure
epoxide.
Epoxidation of 8a using trichloroacetone TCA 5. Trichloroacetone
5 (0.089 g, 0.062 mL, 0.55 mmol) was added to a stirred solution
of substrate 8a (0.145 g, 0.5 mmol) in 17 mL of 50% aqueous aceto-
nitrile. A homogeneous mixture of Oxone™ (0.369 g, 0.6 mmol)
and NaHCO3 (0.126 g, 1.5 mmol) was added to the reaction mix-
ture in one portion at rt. The reaction was monitored by TLC and
the resulting suspension was treated with water (10 mL) after
0.5 h. The reaction mixture was extracted with Et2O (3 ꢂ 25 mL).
The combined organic layers was washed with brine (15 mL), dried
over anhydrous Na2SO4 ,and evaporated to give the crude epoxide.
Flash chromatography over silica-gel (230–400 mesh) column
eluting 25% of EtOAc in petroleum ether afforded pure epoxides
9a (0.138 g) as a non-separable mixture of diastereomers in 90%
yield.
Non-separable mixture of diastereomers; white solid, mp 145–
165 °C; IR (KBr, cmꢀ1): 714, 796, 835, 901, 905, 1018, 1057, 1093,
1110, 1202, 1217, 1229, 1268, 1282, 1307, 1375, 1391, 1401, 1439,
1491, 1717 (CO), 1783 (CO), 2926, 2963; 1H NMR (400 MHz,
CDCl3):
d 0.80–0.90 (m, 6H), 2.32–2.45 (m, 1H), 3.95 (d,
J = 1.6 Hz, 0.65H), 3.99 (d, J = 1.6 Hz, 0.35H), 4.18–4.26 (m, 1H),
4.26–4.37 (m, 1H), 4.37–4.50 (m, 1H), 4.64 (d, J = 1.6 Hz, 1H),
7.15–7.35 (m, 4H); 13C NMR (100 MHz, CDCl3): d (major isomer)
14.6, 17.8, 28.1, 56.7, 58.3, 58.5, 64.2, 127.5 (2C), 128.8 (2C),
133.3, 134.9, 154.1, 167.1; 13C NMR (100 MHz, CDCl3): d (minor
isomer) 14.7, 17.9, 28.3, 56.2, 58.4, 58.8, 64.5, 127.6 (2C), 128.8
(2C), 133.2, 134.9, 154.0, 167.0; Anal. Calcd for C15H16ClNO4: C,
58.16; H, 5.21; N, 4.52. Found: C, 58.46; H, 5.35; N, 4.37.
4.2.4. (4S,20S,30R)-3-(30-Phenyl-oxiranyl)-[4-(1-methylethyl)-2,2-
dimethyl-oxazolidin-3-yl]-methanone 11
White solid, mp 96–97 °C; ½a D26
¼ þ64:3 (c 0.5, CHCl3); IR (KBr,
ꢁ
cmꢀ1): 698, 755, 887, 1064, 1246, 1323, 1390, 1443, 1462, 1653
(CO), 2968, 3063; 1H NMR (400 MHz, CDCl3): d 0.80 (d, J = 7.2 Hz,
3H), 0.91 (d, J = 7.2 Hz, 3H), 1.58 (s, 3H), 1.70 (s, 3H), 1.80–1.95 (m,
1H), 3.48 (d, J = 1.2 Hz, 1H), 3.85–4.02 (m, 3H), 4.08 (d, J = 1.2 Hz,
1H), 7.20–7.45 (m, 5H); 13C NMR (50 MHz, CDCl3): d 17.4, 19.3,
22.9, 25.6, 31.8, 57.99, 58.09, 61.9, 64.9, 96.0, 125.5 (2C), 128.59
(2C), 128.69 (2C), 135.4, 163.8; Anal. Calcd for C17H23NO3: C,
70.56; H, 8.01; N, 4.84. Found: C, 70.69; H, 7.83; N, 4.71.
4.2.5. (2R,20R,30S)-N-[30-{(4-Methoxyphenyl) oxyranyl}metha-
none]bornanesultam 13a
Recrystallization from 30% ethyl acetate in hexane provided a
pure diastereoisomer (dr >99:1) as a white solid, mp 131–132 °C;
½
a 2D9
ꢁ
¼ ꢀ167:8 (c 0.5, CHCl3); IR (KBr, cmꢀ1): 540, 759, 1031,
1067, 1139, 1169, 1227, 1243, 1255, 1275, 1336, 1412, 1518,
1616, 1690 (CO), 2961; 1H NMR (200 MHz, CDCl3): d 0.97 (s, 3H),
1.19 (s, 3H), 1.30–1.50 (m, 2H), 1.75–2.00 (m, 3H), 2.00–2.25 (m,
2H), 3.41 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 3.79 (s,
3H), 3.82–4.00 (m, 1H), 4.01 (d, J = 1.6 Hz, 1H), 4.08 (d, J = 1.6 Hz,
1H), 6.87 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d 19.8, 20.8, 26.4, 32.8, 38.1, 44.7, 47.8, 49.3,
52.9, 55.2, 56.6, 59.3, 65.1, 114.0 (2C), 126.7, 127.4 (2C), 160.1,
166.5; Anal. Calcd for C20H25NO5S: C, 61.36; H, 6.44; N, 3.58.
Found: C, 61.56; H, 6.13; N, 3.29.
4.2.1. (4S,20S,30R) and (4S,20R,30S)-3-[30-(4-Methoxyphen yl)-
oxiranecarbonyl]-4-(1-methylethyl)-2-oxazolidinone 9a
Non-separable mixture of diastereomers; white solid, mp 145–
165 °C. IR (KBr, cmꢀ1): 574, 714, 776, 808, 836, 901, 975, 1030,
1055, 1112, 1176, 1210, 1253, 1303, 1373, 1386, 1410, 1438,
1519, 1615, 1709 (CO), 1782 (CO), 2968; 1H NMR (400 MHz,
CDCl3): d 0.85–1.0 (m, 6H), 2.38–2.55 (m, 1H), 3.80 (s, 3H), 3.99
(d, J = 1.2 Hz, 0.57H), 4.03 (d, J = 1.6 Hz, 0.43H), 4.25–4.32 (m,
1H), 4.32–4.45 (m, 1H), 4.45–4.55 (m, 1H), 4.79 (d, J = 1.6 Hz,
1H), 6.85–6.95 (m, 2H), 7.25–7.35 (m, 2H); 13C NMR (100 MHz,
CDCl3): d (major isomer) 14.6, 17.8, 28.1, 55.3, 56.4, 58.3, 59.2,
64.1, 114.0 (2C), 126.6, 127.6 (2C), 154.0, 160.2, 167.6; 13C NMR
(100 MHz, CDCl3): d (minor isomer) 14.7, 17.9, 28.3, 55.3, 56.0,
58.7, 59.1, 64.4, 114.0 (2C), 126.6, 127.7 (2C), 154.1, 160.2, 167.4;
Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C,
62.67; H, 6.44; N, 4.38.
4.2.6. (2R,20R,30S) and (2R,20S,30R)-N-[(30-Phenyl- oxiran-
yl)methanone]bornanesultam 13b
Non-separable mixture of diastereomers; white solid, mp 135–
160 °C; IR (KBr, cmꢀ1): 536, 695, 760, 1070, 1138, 1167, 1225,
1241, 1278, 1332, 1420, 1458, 1560, 1654, 1689 (CO), 2928,
2968, 3014; 1H NMR (400 MHz, CDCl3): d 0.98 (s, 3H), 1.19 (s,
3H), 1.30–1.46 (m, 2H), 1.85–2.0 (m, 3H), 2.05–2.25 (m, 2H), 3.43
(d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 3.90–4.0 (m, 1H,),
4.07 (d, J = 1.2 Hz, 0.82H), 4.09 (d, J = 1.2 Hz, 0.82H), 4.14 (s,
0.18H), 4.18 (s, 0.18H), 7.30–7.45 (m, 5H); 13C NMR (100 MHz,
CDCl3): d (major isomer) 19.8, 20.8, 26.4, 32.8, 38.1, 44.6, 47.8,
49.3, 52.9, 56.6, 59.3, 65.1, 125.9 (2C), 128.5 (2C), 128.8, 134.7,
166.5; Anal. Calcd for C19H23NO4S: C, 63.13; H, 6.41; N, 3.88.
Found: C, 62.85; H, 6.23; N, 3.71.
4.2.2. (4S,20S,30R) and (4S,20R,30S)-3-(30-Phenyl-oxiranecarbo-
nyl)-4-(1-methylethyl)-2-oxazolidinone 9b
Non-separable mixture of diastereomers; white solid, mp 76–
86 °C. IR (KBr, cmꢀ1): 697, 716, 772, 900, 912, 1022, 1057, 1095,
1109, 1202, 1216, 1265, 1296, 1307, 1353, 1373, 1383, 1390,
1400, 1422, 1460, 1712 (CO), 1780 (CO), 2970; 1H NMR
(400 MHz, CDCl3): d 0.85–1.05 (m, 6H), 2.35–2.55 (m, 1H), 4.04
(d, J = 1.6 Hz, 0.56H), 4.08 (d, J = 1.6 Hz, 0.44H), 4.18–4.30 (m,
1H), 4.30–4.45 (m, 1H), 4.45–4.55 (m, 1H), 4.78 (d, J = 1.2 Hz,
1H), 7.27–7.45 (m, 5H); 13C NMR (100 MHz, CDCl3): d (major iso-
mer) 14.6, 17.9, 28.2, 56.6, 58.4, 59.3, 64.2, 126.2 (2C), 128.7
(2C), 129.1, 134.8, 154.1, 167.5; 13C NMR (100 MHz, CDCl3): d
(minor isomer) 14.8, 18.0, 28.4, 56.1, 58.8, 59.3, 64.5, 126.3 (2C),
128.7 (2C), 129.1, 134.8, 154.0, 167.4; Anal. Calcd for C15H17NO4:
C, 65.44; H, 6.22; N, 5.09. Found: C, 65.64; H, 6.01; N, 5.31.
4.3. Synthesis of methyl-3-(4-methoxyphenyl)glycidate 2
Methanol (0.02 ml) was taken with 3 ml of dry Et2O in a 25 ml
two necked flask under an argon atmosphere. The flask was then
placed in a low temperature bath (ꢀ78 °C) and nBuLi (0.16 ml,
1.6 M solution in hexane, 0.26 mmol) was added slowly. After
10 min a solution of epoxide (0.26 mmol) in dry Et2O (5 mL) was

S. Hajra, M. Bhowmick / Tetrahedron: Asymmetry 21 (2010) 2223–2229
2229
added dropwise and the reaction mixture was stirred for an addi-
tional 10 min at ꢀ78 °C. The reaction was quenched with saturated
aqueous NH4Cl solution (3 mL), extracted with Et2O (3 ꢂ 10 mL),
washed with brine and dried over anhydrous Na2SO4. Removal of
the solvent and flash column chromatography over silica-gel af-
fords pure epoxides.
IIT Guwahati under the FIST program (Sanction No.: SR/FST/CSII-
007/2003) for extending support for single XRD data. We are also
thankful to Dr. S. Khatua for the single crystal X-ray analysis. MB
likes to thank IIT, Kharagpur and CSIR, New Delhi for his
fellowship.
References
4.3.1. Methyl-(2R,3S)-3-(4-methoxyphenyl)glycidate (ꢀ)-29
Gummy liquid; ½a D29
ꢁ
¼ ꢀ209:5, (c 1.0, MeOH) {lit. ½a D24
¼ ꢀ205
ꢁ
1. (a) Yang, D.; Ye, X.-Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121, 5579–5580; (b)
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R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem. 1988, 53, 3890–3891; (c)
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6757; (d) Murray, R. W.; Singh, M.; Jeyaraman, R. J. Am. Chem. Soc. 1992, 114,
1346–1351.
(c 1.0, MeOH)}; 1H NMR (400 MHz, CDCl3): d 3.51 (d, J = 1.2 Hz,
1H), 3.81 (s, 3H), 3.82 (s, 3H), 4.05 (d, J = 1.2 Hz, 1H), 6.89 (d,
J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 52.5, 55.3, 56.5, 57.9, 114.1 (2C), 126.6, 127.2 (2C), 160.2, 168.8.
4.4. X-ray crystallographic analysis of 11
A single crystal of 6 was grown from 30% ethyl acetate/hexane;
C
17H23NO3, Mr = 289.36, Monoclinic, space group C2, a = 19.92
97(6) Å, b = 7.2983(2) Å, c = 13.7430 (5) Å; V = 1715.38(9) Å3, Z = 4,
Dcalcd = 1.120 Mg/m3, X-ray crystallographic data were collected at
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1980, 45, 4758–4760; (b) Adam, W.; Hadjiarapoglou, L. P.; Smerz, A. Chem. Ber.
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Tetrahedron Lett. 1994, 35, 1577–1580.
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8. (a) Fan, C. L.; Lee, W.-D.; Teng, N.-W.; Sun, Y.-C.; Chen, K. J. Org. Chem. 2003, 68,
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Imashiro, R.; Hatsuda, M.; Seki, M. J. Org. Chem. 2002, 67, 4599–4601.
10. Crystallographic data (excluding structure factors) for the structure have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 742654.
11. (a) Oppolzer, W.; Poli, G.; Starkmann, C.; Bernardelli, G. Tetrahedron Lett. 1988,
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67, 1397; (c) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585.
273 K with a Mo Ka radiation source (k = 0.71073 Å) by using CCD
diffractometer equipped with a graphite monochromator. The SMART
software was used for data collection, for indexing the reflections
andfordeterminingtheunitcellparameters; thecollecteddatawere
integrated by using the SAINT software. The structures were solved by
direct methods and refined by full matrix least-squares calculations
(F2) by using the SHELXL-97 software. The final R value is 0.0564
(RW = 0.1687) for 4164 reflections [I > 2r(I)]. Crystallographic data
for the structure in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
CCDC 742654. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223 336033 or email: deposit@ccdc.cam.ac.Uk).
Acknowledgments
We wish to thank DST, New Delhi for providing financial sup-
port and for providing XRD facility to the Department of Chemistry,