Influence of polymerization degree of poly-l-leucine catalyst and substituent effect on the Julia-Colonna asymmetric epoxidation of benzalacetophenones

Article abstract of DOI:10.3987/COM-04-S(P)5

The Julia-Colonna asymmetric epoxidation reaction of substituted benzalacetophenone afforded the corresponding epoxide with high yield and high enantioselectivity, catalyzed by the specified length of poly-l-leucine (chain length n > 15). Poly-l-leucine catalysts have been prepared by the polymerization reaction of l-leucine-NCA with initiators (BnONa, n-BuNH₂, H₂O) and characterized by the MALD1-TOF Mass and IR analysis.

Full text of DOI:10.3987/COM-04-S(P)5

HETEROCYCLES, Vol. 64, 2004
129
HETEROCYCLES, Vol. 64, 2004, pp. 129 - 141
Received, 3rd March, 2004, Accepted, 15th April, 2004, Published online, 16th April, 2004
INFLUENCE OF POLYMERIZATION DEGREE OF POLY-L-LEUCINE
CATALYST AND SUBSTITUENT EFFECT ON THE JULIÁ-COLONNA
ASYMMETRIC EPOXIDATION OF BENZALACETOPHENONES
Ryukichi Takagi, Shahnaz Begum, Akiko Siraki, Arata Yoneshige,
Kin-ichirou Koyama, and Katsuo Ohkata*
Department of Chemistry, Graduate School of Science, Hiroshima University,
1
-3-1 Kagamiyama, Higashi-Hiroshima, 739-8526, Japan
Abstract – The Juliá-Colonna asymmetric epoxidation reaction of substituted
benzalacetophenone afforded the corresponding epoxide with high yield and high
enantioselectivity, catalyzed by the specified length of poly-L-leucine (chain
length n > 15). Poly-L-leucine catalysts have been prepared by the polymerization
2 2
reaction of L-leucine-NCA with initiators (BnONa, n-BuNH , H O) and
characterized by the MALDI-TOF Mass and IR analysis.
INTRODUCTION
The epoxide functionality has frequently been demonstrated to be a versatile and useful moiety for
1
organic synthesis. For this reason the synthesis of chiral oxirans is still a challenging target in the area of
asymmetric induction. Recently, we have investigated the asymmetric induction in epoxidations and
2
cyclopropanations by means of the (-)-8-phenylmenthyl moiety as a chiral auxiliary. In the Juliá-Colonna
asymmetric epoxidation reaction of benzalacetophenone, catalyzed by the length-defined poly-L-leucine
(n > 15), the enantioselectivity is very attractive and high. This asymmetric epoxidation is interesting
owing to its enzymatic behavior with respect to the substrate specificity. The Juliá-Colonna asymmetric
3
epoxidation methodology has been improved with the following viewpoint in organic synthesis: (1)
Two-phase oxidation system (urea-hydrogen peroxide complex, DBU, poly-L-leucine, THF) required
2 2
shorter reaction time than the original three-phase oxidation system (30% H O , aq. NaOH,
4
poly-L-leucine, toluene). (2) The Juliá-Colonna epoxidation of various type of enones which are different
5
from benzalacetophenone have been developed. (3) The quality of the poly-leucine catalysts was
_
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
This paper is dedicated to Dr. Pierre Potier on the occasion of his 70th birthday.

130
HETEROCYCLES, Vol. 64, 2004
6
improved by the immobilization of polyleucine on CLAMPS (cross-linked aminomethylpolystyrene). (4)
7
Recently, soluble poly-peptides have been tested for activity in Juliá-Colonna epoxidation.
On the other hand, the mechanistic features of the Juliá-Colonna asymmetric epoxidation is not well
known. In the Juliá-Colonna asymmetric epoxidation by means of oligo-L-leucine catalysts of defined
length (degree varying from 5 to 20), the higher degree of polymerization of catalyst made the yields and
8
selectivities higher. Optimal conditions require leaving the N-terminus unprotected and having the
number of leucine units at least ca. 15. A related and intriguing study on polymer supported
oligo-L-leucine catalysts of specified length (degrees of 10 and 20 of varying enantiomer composition)
9
was disclosed by Roberts and his co-workers. The same tendency was found in the asymmetric
epoxidation using polymer supported oligo-L-leucine catalysts. Our IR spectral measurements of the
length defined oligo-L-leucines suggested that α-helical structure of the catalysts played an important role
on the asymmetric induction. Here, we report the structural features of the poly-L-leucine catalysts and
substituent effect on the asymmetric epoxidation of benzalacetophenones.
RESULTS AND DISCUSSION
The poly-L-leucines were prepared by polymerization of L-leucine N-carboxyanhydride (L-Leu-NCA)
1
0
(
Scheme 1). Reaction of benzyloxycarbonyl-L-leucine (Cbz-L-Leu) with oxalyl chloride afforded
L-Leu-NCA. The subsequent polymerization of L-Leu-NCA with initiators (BnONa, n-BuNH , H O)
afforded poly-L-leucine catalysts (I-III) (Table 1). The amide I region in the IR spectra of poly-L-leucine
I-II) in the solid state was shown in Figure. 1. The IR spectra of poly-L-leucine (IIa, IIb, IIc, and IId)
2
2
(
-1
-1
11
showed bands at 1630 cm assigned to β-sheet structure and 1655 cm assigned to helical structure.
The IR spectra of the amide I region of poly-L-leucine (I and IIe) showed strong absorption bands at 1655
-1
-1
cm assigned to the helical structure and the shoulder bands at 1630 cm assigned to β-sheet structure.
a
c
b
H-L-Leu-OH
Cbz-L-Leu-OH
L-Leu-NCA
H-L-(Leu) -X
n
I-III
I: X = OBn, II: X = nBuN, III: X = OH
2
Scheme 1. Reagents and conditions: (a) CbzCl, 2N NaOH; (b) (COCl) , benzene; (c) initiator
(
BnONa For I, n-BuNH for II, H O for III, MeCN).
2
2

HETEROCYCLES, Vol. 64, 2004
131
Table 1. Synthesis of poly-L-leucine catalysts (I-III)
polymerization degree
most frequent second frequent
entry
initiator
X
product
distribution of
polymerization
1
2
3
4
5
6
BnOH/NaH BnO
I
7-12
4-12
2-23
3-23
3-22
5-20
---
8
12
n-BuNH
n-BuNH
n-BuNH
n-BuNH
n-BuNH
2
2
2
2
2
n-BuNH
n-BuNH
n-BuNH
n-BuNH
n-BuNH
OH
IIa
IIb
IIc
IId
IIe
III
7
6
7
7
9
8
17
16
15
16
a)
7
H
2
O
a
1
average degree of polymerization estimated by H NMR
I
IIc
IId
IIa
IIe
IIb
1800
1600
Wavenumber /cm-1
1800
1600
-1
Wavenumber /cm
Figure 1. IR spectra of poly-L-leucine catalysts (I and IIa-e).
The poly-L-leucine catalysts (I-III) were characterized by MS spectra using MALDI-TOF technique
Table 1 and Figure 2). The mass weight (m/z) of the poly-L-leucine catalyst (I) distributed from 945 (n =
) to 1504 (n = 12). The most frequent polymerization degrees was 1035 (n = 8) and the second
(
7
frequent polymerization degree was 1488 (n = 12) (Table 1, entry 1). The distribution of polymerizaton of
the poly-L-leuine catalyst (IIa) was narrow (n = 4 to 12) compared with that of IIb-e and the most
frequent polymerization degree was n = 7 (Table 1, entry 2). The distribution of polymerization of the
poly-L-leucine catalysts (IIb-e) was relatively wide and more highly polymerized poly-L-leucine (n > 15)
was contained in the catalysts (Table 1, entries 3-6). The average degree of polymerization in

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HETEROCYCLES, Vol. 64, 2004
1
poly-L-leucine (III) was n = 8, which was estimated by integral values of H NMR spectrum (Table 1,
entry 7).
Figure 2. MS spectra of poly-L-leucine catalysts (I and IIa-e).

HETEROCYCLES, Vol. 64, 2004
133
O
H
S
poly-L-leucine catalyst (I-III)
O
O
2
R
R2
R
H
3
0% aq. H O , 10M-NaOH,
2 2
1
R
:
1
toluene, 25 ºC, 24 h
R
2 :
4a :
1
2
1
2
1
R = H, R = H
R = H, R = H
R = o-MeO, R = H
R = m-MeO, R = H
R = p-MeO, R = H
R = o-Me, R = H
R = m-Me, R = H
R = p-Me, R = H
R = o-Cl, R = H
R = m-Cl, R = H
R = p-Cl, R = H
R = H, R = o-MeO
R = H, R = m-MeO
R = H, R = p-MeO
R = H, R = o-Me
R = H, R = m-Me
R = H, R = p-Me
1
2
1
2
3
a :
b :
c :
a :
b :
c :
a :
b :
c :
a :
b :
c :
1a :
1b :
1c :
3a :
3b :
3c :
R = o-MeO, R = H
1
2
1
2
3
3
5
5
5
7
7
7
R = m-MeO, R = H
4b :
1
2
1
2
R = p-MeO, R = H
4c :
1
2
1
2
R = o-Me, R = H
6a :
6b :
1
2
1
2
R = m-Me, R = H
1
2
1
2
R = p-Me, R = H
6c :
1
2
1
2
R = o-Cl, R = H
8a :
8b :
1
2
1
2
R = m-Cl, R = H
1
2
1
2
R = p-Cl, R = H
8c :
1
2
1
2
9
9
9
R = H, R = o-MeO
10a :
10b :
10c :
12a :
12b :
12c :
14a :
14b :
14c :
1
2
1
2
R = H, R = m-MeO
1
2
1
2
R = H, R = p-MeO
1
2
1
2
1
R = H, R = o-Me
1
2
1
2
1
R = H, R = m-Me
1
2
1
2
1
1
R = H, R = p-Me
1
2
1
2
R = H, R = o-Cl
R = H, R = o-Cl
R = H, R = m-Cl
R = H, R = p-Cl
1
2
1
2
1
R = H, R = m-Cl
1
2
1
2
1
R = H, R = p-Cl
Scheme 2.
Juliá-Colonna asymmetric epoxidation of benzalacetophenones catalyzed by
poly-L-leucine.
Epoxidation reactions of benzalacetophenone (1) with 30% aqueous H O /10M-NaOH in the presence of
2
2
poly-L-leucine catalysts were carried out (Scheme 2). Table 2 shows the stereoselectivity in the
epoxidation of 1 catalyzed by poly-L-leucine (I-III). In the presence of poly-L-leucine catalysts (I and
IIa), chemical yields were very low (Table 2, entries 1, 2). The catalytic low activity may be attributed to
the low degree of polymerization. Moreover, the enantioselectivity of the reaction using the
poly-L-leucine catalyst (IIa) was considerably lower than that of the other catalysts (Table 2, entry 2).
Both the chemical yield and enantioselectivity of the product in the reaction using poly-L-leucine (IIb-e
Table 2. Asymmetric epoxidation of benzalacetophenone catalyzed by various poly-L-leucine
entry
poly-L-leucine
%ee
90
70
92
91
93
90
93
yield %
39
18
75
83
87
85
73
1
2
3
4
5
6
7
I
IIa
IIb
IIc
IId
IIe
III

134
HETEROCYCLES, Vol. 64, 2004
and III) were significantly higher relative to those of original Juliá-Colonna catalysts (Table 2, entries
-7). The functional groups (n-BuN and OH) at C-terminus are more favorable than the BnO group for
3
the asymmetric induction and the preparation of the catalyst.
Judging from the asymmetric induction of the epoxidation along with the IR spectral features, the longer
1
2
the chain length of the poly-L-leucine is, the higher the distribution of α-helix structures. The α-helical
structure of the catalysts played an important role on the asymmetric induction.
The asymmetric epoxidation of a series of substituted benzalacetophenones by the poly-L-leucine catalyst
(
III) was examined (Tables 3 and 4). Both the chemical yield and enantioselectivity in the reaction of
p-substituted benzalacetophenones by the poly-L-leucine catalyst (III) were comparable to those of the
unsubstituent substrate (1) (Table 3, entries 4, 7, 10; Table 4, entries 4, 7, 10). In the asymmetric
epoxidation reaction of m-substituted benzalacetophenones by the poly-L-leucine catalyst (III), the
enantioselectivity was also high (Table 3, entries 3, 6, 9; Table 4, entries 3, 6, 9), while the reaction yields
Table 3. Epoxidation of substituted benzalacetophenones catalyzed by poly-L-leucines catalyst (III)
a
b
entry
substrate
1
R
H
1
R
2
product
2
yield (%)
73
%ee
93
81
92
97
81
94
97
76
92
94
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
5a
5b
5c
7a
7b
o-MeO
m-MeO
p-MeO
o-Me
m-Me
p-Me
o-Cl
4a
4b
4c
6a
6b
6c
8a
8b
8c
27 (64)
58 (82)
72 (97)
27 (49)
47 (53)
84 (84)
48 (76)
74 (95)
77 (93)
m-Cl
p-Cl
10
7c
a) Reaction yield in parenthesis.
b) The ratios were determined by HPLC analysis using a chiralcel-OD.
Table 4. Epoxidation of substituted benzalacetophenones catalyzed by poly-L-leucines catalyst (III)
a
b
entry
substrate
R1
R2
product
yield (%)
%ee
1
2
3
4
5
6
7
8
9
1
9a
9b
9c
11a
11b
11c
13a
13b
13c
H
H
H
H
H
H
H
H
H
H
H
2
73
93
67
90
85
87
98
93
54
95
94
o-MeO
m-MeO
p-MeO
o-Me
m-Me
p-Me
o-Cl
10a
10b
10c
12a
12b
12c
14a
14b
14c
39 (43)
45 (54)
66 (69)
46 (57)
65 (81)
66 (76)
92 (97)
83 (92)
87 (91)
m-Cl
p-Cl
10
a) Reaction yield in parenthesis.
b) The ratios were determined by HPLC analysis using a chiralcel-OD.

HETEROCYCLES, Vol. 64, 2004
135
were comparable to or lower than that of the unsubstituted substrate (1). The o-substituent remarkably
affected to both the yield and the enantioselectivity (Table 3, entries 2, 5, 8; Table 4, entries 2, 5, 8). The
reaction was deaccelerated by the o-substituent and the favorable attack of the nucleophile may be
disturbed to lower the enantioselectivity.
Conclusion
Our results supported the original speculations made by Juliá and Colonna that α-helical structure of the
catalysts was important for the high asymmetric induction. The o-hetero substituent on phenyl group
attached at vinyl position of benzalacetophenone influences both the reactivity and the enantioselectivity.
EXPERIMENRAL
General Methods
NMR spectra were recorded on a JEOL GSX-270 or a JMN-LA500 instrument and calibrated using TMS
as an internal reference (δ=0.0). IR spectra were recorded on a JASCO-FT/IR7300 spectrophotometer.
High-resolution mass spectra (HRMS) were recorded on a JEOL SX-102A mass spectrometer under
fast-atom bombardment (FAB) conditions. MALDI-TOF MS spectra were recorded on a BRUKER
REFLEX.
1
3
General Procedure for the Preparation of L-Leucine-NCA
Benzyloxyacarbonyl-L-leucine (Cbz-L-Leu) (4.61 g, 17.4 mmol) was dissolved in benzene (20 mL).
COCl) (2 mL) was slowly added to the solution and the reaction mixture was warmed at 60 to 70 ºC for
5 min. After the reaction mixture was cooled to 25 ºC, hexane-ether (1 : 1) was added to the mixture.
(
2
1
2 2
The white solid which formed was filtered and recrystallized from CH Cl /hexane (2.85 g): mp 72-73 ºC:
1
H NMR (500 MHz, CDCl ) δ 0.99 (3 H, d, J = 6.4 Hz), 1.01 (3 H, d, J = 6.4 Hz), 1.69 (1 H, m), 1.83 (2
3
H, m), 4.34 (1 H, dd, J = 4.4, 8.8 Hz), 6.19 (1 H, m).
General Procedure for the Polymerization of L-Leucine-NCA
Appropriate amount of initiator in CH CN was added to a solution of L-leucine-NCA in CH CN. The
3
3
reaction mixture was stirred at 25 ºC for 5 days. The solvent was evaporated under reduced pressure. Dry
Et O was added to the residue to form a white solid, which was formed and filtered. The white soiled was
washed with ether and CH Cl and used for subsequent reactions without further purification.
2
2
2
General Procedure for the Asymmetric Epoxidation Using Oligo-L-Leucine as Catalyst

136
HETEROCYCLES, Vol. 64, 2004
2 2
An aliquot (1.7 mL) of a solution of NaOH (0.8 g, 20 mmol) in 30% aqueous H O (10 mL, 88.2 mmol)
was added to a mixture of oligo-L-leucine catalyst (100 mg) and benzalacetophenones (1) (100 mg, 0.48
mmol) in toluene (1.7 mL) at 0 °C. The mixture was allowed to warm to rt and was vigorously stirred
for 24 h. The insoluble catalyst was filtered off and the filtrate was washed with water and brine, dried
2 4
over Na SO , and evaporated. The crude product was purified by preparative TLC [silica gel, petroleum
ether/ether = 10 : 1 (v/v)] to give pure sample (2). The enantiomeric excess of the product (2) was
determined by HPLC analysis [hexane/2-propanol = 9 : 1 (v/v), 254 nm] using chiralcel OD (Daicel
Chemical Industries, Ltd.).
1
4
trans-(2R,3S)-2,3-Epoxy-1,3-diphenylpropan-1-one (2)
2
5
[
α] = -300° (c 0.06, MeOH); CD (iPrOH) ∆ε318 = -5.0; ∆ε257 = -6.6; ∆ε247 = 0; ∆ε231 = 7.6 (C = 0.043
D
1
mg/ml); H NMR (270 MHz, CDCl
3
) δ 4.08 (1 H, d, J = 2.0 Hz), 4.29 (1 H, d, J = 2.0 Hz), 7.43-8.06 (10
1
3
H, m); C NMR (68 MHz, CDCl
3
) δ 58.4, 60.7, 124.0 (x2), 125.6, 128.3, 128.7, 128.8, 129.1, 130.0,
+
1
34.0, 134.8, 135.3, 137.6, 192.5; HRMS (EI) Calcd for C15
H
12
O
2
[M ] 224.0837. Found 224.0843.
1
5
trans-(2R,3S)-2,3-Epoxy-1-(2'-methoxyphenyl)-3-phenylpropan-1-one (4a)
2
5
1
[
α] = -13.0° (c 0.23, hexane); H NMR (270 MHz, CDCl
3
) δ 3.59 (3 H, s, OMe), 4.01 (1 H, d, J = 2.0
Hz), 4.31 (1 H, d, J = 2.0 Hz), 7.08-7.84 (9 H, m); C NMR (68 MHz, CDCl ) δ 55.6, 59.8, 64.5, 111.6,
21.1, 125.8, 126.0, 127.3, 128.4, 128.6, 128.7, 130.7, 134.9, 136.5, 159.6, 194.9; HRMS (EI) Calcd for
D
1
3
3
1
+
C
16 14 3
H O [M ] 254.0943. Found 254.0955.
trans-(2R,3S)-2,3-Epoxy-1-(3'-methoxyphenyl)-3-phenylpropan-1-one (4b)
2
5
1
[
α] = -199.3° (c 0.30, hexane); H NMR (270 MHz, CDCl
3
) δ 3.84 (3 H, s, OMe), 4.07 (1 H, d, J = 1.5
Hz), 4.28 (1 H, d, J = 1.5 Hz), 7.14-7.59 (9 H, m); C NMR (68 MHz, CDCl ) δ 55.4, 59.4, 61.0, 112.2,
12.4, 120.5, 120.9, 125.7, 128.7, 129.0, 129.5, 129.8, 135.4, 136.7, 159.9, 190.8; HRMS (EI) Calcd for
D
1
3
3
1
+
C
16 14 3
H O [M ] 254.0943. Found 254.0953.
1
6
trans-(2R,3S)-2,3-Epoxy-1-(4'-methoxyphenyl)-3-phenylpropan-1-one (4c)
2
5
1
[
α] = -231.2° (c 0.23, hexane); H NMR (270 MHz, CDCl ) δ 3.87 (3 H, s, OMe), 4.06 (1 H, d, J = 2.0
3
D
1
3
Hz), 4.25 (1 H, d, J = 2.0 Hz), 6.59 (2 H, d, J = 8.8 Hz), 7.36-7.40 (5 H, m), 8.01 (2 H, d, J = 8.8 Hz); C
NMR (68 MHz, CDCl
3
) δ 55.6, 59.2, 60.9, 113.8 (x2), 114.1, 125.8, 128.2, 128.6, 129.0, 130.8 (x2),
+
131.4, 135.8, 164.3, 191.4; HRMS (EI) Calcd for C16
H
14
O
3
[M ] 254.0943. Found 254.0952.
4
d
trans-(2R,3S)-2,3-Epoxy-1-(2'-methylphenyl)-3-phenylpropan-1-one (6a)

HETEROCYCLES, Vol. 64, 2004
137
2
5
1
[
α] = -125.6° (c 0.20, hexane); H NMR (270 MHz, CDCl
3
) δ 2.54 (3 H, s, CH
3
), 4.04 (1 H, d, J = 2.0
D
1
3
Hz), 4.11 (1 H, d, J = 2.0 Hz), 7.23-7.69 (9 H, m); C NMR (68 MHz, CDCl
3
) δ 21.0, 59.5, 62.4, 125.5,
125.8, 127.1, 128.5, 128.6, 128.8, 128.9, 129.0, 132.1, 132.3, 135.5, 138.9, 196.6; HRMS (EI) Calcd for
+
C
16 14 2
H O [M ] 238.0994. Found 238.0999.
1
7
trans-(2R,3S)-2,3-Epoxy-1-(3'-methylphenyl)-3-phenylpropan-1-one (6b)
2
5
1
[
α] = -169.2° (c 0.15, hexane); H NMR (270 MHz, CDCl
3
) δ 2.38 (3 H, s, CH
Hz), 4.26 (1 H, d, J = 2.0 Hz), 7.31-7.78 (9 H, m); C NMR (68 MHz, CDCl ) δ 21.3, 59.4, 60.9, 125.6
x2), 125.8 (x2), 128.8 (x2), 129.0 (x2), 134.8 (x2), 135.6, 138.8, 193.2; HRMS (EI) Calcd for C16
3
), 4.04 (1 H, d, J = 2.0
D
1
3
3
(
[
14 2
H O
+
M ] 238.0994. Found 238.0988.
16
trans-(2R,3S)-2,3-Epoxy-1-(4'-methylphenyl)-3-phenylpropan-1-one (6c)
2
5
1
[
α] = -165.8° (c 0.24, hexane); H NMR (270 MHz, CDCl
3
3
) δ 2.39 (3 H, s, CH ), 4.06 (1 H, d, J = 2.0
D
1
3
Hz), 4.25 (1 H, d, J = 2.0 Hz), 7.25 (2 H, d, J = 8.5 Hz), 7.31-7.37 (5 H, m), 7.88 (2 H, d, J = 8.5 Hz); C
NMR (68 MHz, CDCl
3
) δ 21.8, 59.3, 60.9, 125.8 (x2), 126.6, 128.4, 128.5, 128.7, 129.0, 129.2, 129.6,
+
133.1, 135.6, 145.1, 192.6; HRMS (EI) Calcd for C16
H
14
O
2
[M ] 238.0994. Found 238.0998.
4
d
trans-(2R,3S)-2,3-Epoxy-1-(2'-chlorophenyl)-3-phenylpropan-1-one (8a)
2
5
1
[
α] = -157.3° (c 0.25, hexane); H NMR (270 MHz, CDCl
3
) δ 4.10 (1 H, d, J = 1.7 Hz), 4.16 (1 H, d, J
D
1
3
=
1.7 Hz), 7.30-7.64 (9 H, m); C NMR (68 MHz, CDCl ) δ 60.4, 62.8, 125.8, 127.1, 128.4, 128.5, 128.6,
3
3
5
+
1
11 2
28.8, 129.0, 130.4, 130.6, 132.1, 135.2, 136.5, 196.3, HRMS (EI) Calcd for C15H O Cl [M ] 258.0448.
Found 258.0444.
trans-(2R,3S)-2,3-Epoxy-1-(3'-chlorophenyl)-3-phenylpropan-1-one (8b)
2
5
1
[
α] = -175.0° (c 0.19, hexane); H NMR (270 MHz, CDCl
3
) δ 4.08 (1 H, d, J = 1.7 Hz), 4.24 (1 H, d, J
D
1
3
=
1.7 Hz), 7.43-8.00 (9 H, m); C NMR (68 MHz, CDCl ) δ 59.5, 61.0, 125.8, 126.5, 128.4 (x2), 128.9,
3
3
5
+
1
29.0, 129.2, 130.2, 133.9, 135.1, 135.3, 136.8, 192.0; HRMS (EI) Calcd for C15
58.0448. Found 258.0473.
11 2
H O Cl [M ]
2
1
6
trans-(2R,3S)-2,3-Epoxy-1-(4'-chlorophenyl)-3-phenylpropan-1-one (8c)
2
5
1
[
α] = -208.4° (c 0.41, hexane); H NMR (270 MHz, CDCl
3
) δ 3.79 (1 H, d, J = 1.7 Hz), 4.24 (1 H, d, J
D
1
3
=
1.7 Hz), 7.43-7.99 (9 H, m); C NMR (68 MHz, CDCl ) δ 59.3, 61.0, 125.7 (x2), 128.7 (x2), 128.8,
3
3
5
+
128.9, 129.2 (x2), 129.7, 133.6, 135.2, 140.4, 192.0; HRMS (EI) Calcd for C15
11 2
H O Cl [M ] 258.0448.
Found 258.0447.

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HETEROCYCLES, Vol. 64, 2004
18
trans-(2R,3S)-2,3-Epoxy-3-(2'-methoxyphenyl)-1-phenyl-3-propan-1-one (10a)
1
H NMR (270 MHz, CDCl ) δ 3.85 (3 H, s, OMe), 4.20 (1 H, d, J = 2.0 Hz), 4.40 (1 H, d, J = 2.0 Hz),
3
1
3
6
1
2
.89-8.04 (9 H, m); C NMR (68 MHz, CDCl
3
) δ 55.4, 55.7, 60.4, 110.3, 120.7, 124.2, 125.5, 128.4 (x2),
+
28.7 (x2), 129.6, 133.8, 135.6, 158.2, 193.7; HRMS (EI) m/z Calcd for C16
H
14
O
3
[M ] 254.0943. Found
54.0942.
trans-(2R,3S)-2,3-Epoxy-3-(3'-methoxyphenyl)-1-phenyl-3-propan-1-one (10b)
1
H NMR (270 MHz, CDCl ) δ 3.82 (3 H, s, OMe), 4.05 (1 H, d, J = 1.7 Hz), 4.28 (1 H, d, J = 1.7 Hz),
3
1
3
6
.90-8.02 (9 H, m); C NMR (68 MHz, CDCl
3
) δ 55.3, 59.3, 60.9, 110.8, 114.7, 118.2, 128.3, 128.5,
+
1
28.1, 129.7, 129.8, 133.7, 135.4, 137.1, 160.1, 193.0; HRMS (EI) Calcd for C16
H
14
O
3
[M ] 254.0943.
Found 254.0943.
19
trans-(2R,3S)-2,3-Epoxy-1-(4'-methoxyphenyl)-3-phenyl-3-propan-1-one (10c)
2
5
1
[
α] = -78.9° (c 0.19, hexane); H NMR (270 MHz, CDCl
3
) δ 3.83 (3 H, s, OMe), 4.02 (1 H, d, J = 1.7
Hz), 4.29 (1 H, d, J = 1.7 Hz), 6.91-8.02 (9 H, m); C NMR (68 MHz, CDCl ) δ 55.2, 55.4, 75.2, 113.6,
13.9, 114.3, 128.4, 128.5, 129.0, 129.2, 129.7, 130.2, 132.0, 133.2, 134.0, 190.8; HRMS (EI) Calcd for
D
1
3
3
1
+
C
16 14 3
H O [M ] 254.0943. Found 254.0949.
20
trans-(2R,3S)-2,3-Epoxy-3-(2'-methylphenyl)-1-phenyl-3-propan-1-one (12a)
2
5
1
[
α] = -39.2° (c 0.16, hexane); H NMR (270 MHz, CDCl
3
3
) δ 2.73 (3 H, s, CH ), 4.22 (2 H, d, J = 1.5
D
1
3
Hz), 7.20-8.07 (9 H, m); C NMR (68 MHz, CDCl
3
) δ 18.8, 57.7, 60.1, 124.2, 126.4, 128.3, 128.5, 128.6,
+
1
28.7, 128.9, 130.1, 133.9, 134.0, 135.5, 136.3, 193.4; HRMS (EI) Calcd for C16
H
14
O
2
[M ] 238.0994.
Found 238.1001.
2
1
trans-(2R,3S)-2,3-Epoxy-3-(3'-methylphenyl)-1-phenyl-3-propan-1-one (12b)
2
5
1
[
α] = -157.9° (c 0.17, hexane); H NMR (270 MHz, CDCl
3
) δ 2.32 (3 H, s, CH
Hz), 4.24 (1 H, d, J 1.7), 7.12-7.96 (9 H, m); C NMR (68 MHz, CDCl ) δ 21.3, 59.4, 60.9, 123.0, 126.2
x2), 128.3 (x2), 128.6, 128.8 (x2), 132.4, 135.4, 135.5, 138.6, 193.1; HRMS (EI) Calcd for C16
3
), 3.98 (1 H, d, J = 1.7
D
1
3
3
(
[
14 2
H O
+
M ] 238.0994. Found 238.0982.
22
trans-(2R,3S)-2,3-Epoxy-3-(4'-methylphenyl)-1-phenyl-3-propan-1-one (12c)
2
5
1
[
α] = -135.0° (c 0.11, hexane); H NMR (270 MHz, CDCl
3
3
) δ 2.32 (3 H, s, CH ), 3.98 (1 H, d, J = 2.0
D
1
3
Hz), 4.23 (1 H, d, J = 2.0 Hz), 7.13-7.64 (9 H, m); C NMR (68 MHz, CDCl ) δ 20.9, 59.1, 60.7, 125.4,
3

HETEROCYCLES, Vol. 64, 2004
139
127.9, 128.5, 128.6, 129.0, 129.3, 129.8, 132.1, 133.6, 135.1, 138.7, 159.1, 192.9; HRMS (EI) Calcd for
+
C
16
H
14
O
2
[M ] 238.0994. Found 238.0986.
23
trans-(2R,3S)-2,3-Epoxy-3-(2'-chlorophenyl)-1-phenyl-3-propan-1-one (14a)
2
5
1
mp 48-49 °C; [α] = -12.1° (c 0.12, hexane); H NMR (270 MHz, CDCl
3
) δ 4.06 (1 H, d, J = 1.7 Hz),
) δ 58.4, 60.7, 124.0, 125.6,
28.3 (x2), 128.7, 128.8, 129.1, 130.0, 134.0, 134.8, 135.3, 137.6, 192.5; HRMS (EI) Calcd for
D
1
3
4
.26 (1 H, d, J = 1.7 Hz), 7.24-8.02 (9 H, m); C NMR (68 MHz, CDCl
3
1
3
5
+
C
15 11 2
H O Cl [M ] 258.0448. Found 258.0440.
17
trans-(2R,3S)-2,3-Epoxy-3-(3'-chlorophenyl)-1-phenyl-3-propan-1-one (14b)
2
5
1
mp 74 °C; [α] = -137.5° (c 0.17, hexane); H NMR (270 MHz, CDCl ) δ 4.17 (1 H, d, J = 2.0 Hz),
3
D
1
3
4
1
2
.41 (1 H, d, J = 2.0 Hz), 7.30-8.07 (9 H, m); C NMR (68 MHz, CDCl
3
) δ 57.0, 59.9, 126.0, 127.2,
+
28.3 (x2), 128.4 (x2), 128.8, 129.2, 129.7, 133.2, 133.9, 135.2, 192.6; MS (EI) m/z 258.0496 [M ],
+
60.0404 [M ].
1
9
trans-(2R,3S)-2,3-Epoxy-3-(4'-chlorophenyl)-1-phenyl-3-propan-1-one (14c)
2
5
1
mp 114 °C; [α] = -168.0° (c 0.45, hexane); H NMR (270 MHz, CDCl
3
) δ 4.06 (1 H, d, J = 2.0 Hz),
D
1
3
4
.25 (1 H, d, J = 2.0 Hz), 7.29-8.01 (9 H, m); C NMR (68 MHz, CDCl
x2), 127.6 (x2), 128.0 (x2), 128.9, 134.0, 134.8, 135.3, 192.7; HRMS Calcd for C15
58.0448. Found 258.0445.
3
) δ 58.6, 60.8, 127.1 (x2), 128.2
3
5
+
(
11 2
H O Cl [M ]
2
ACKNOWLEDGEMENTS
NMR and MS spectral measurements were made using JEOL GSX-270 or JEOL Lambda-500, and JEOL
SX-102A, respectively, at the Natural Science Centre for Basic Research and Development (N-BARD),
Hiroshima University.
REFERENCES AND NOTES
1.
(a) M. Bartok and K. L. Lang, “The Chemistry of Ethers, Crown Ethers, Hydroxyl Groups and Their
Sulpher Analogs, Suplement E,” ed. by S. Patai, John Wiley, New York, 1980, Vol. 2, p. 609. (b) A.
S. Rao, S. K. Paknikar, and J. G. Kirtane, Tetrahedron, 1983, 39, 2323. (c) J. G. Smith, Synthesis,
1984, 629. (d) E. G. Lewars, in “Comprehensive Heterocyclic Chemistry,” ed. by A. R. Katritzky
and C. W. Rees, Pergamon, Oxford, 1984, Vol. 7, p. 95. (e) I. Erden, in “Comprehensive
Heterocyclic Chemistry II,” ed. by A. Padwa, Elsevier, Oxford, 1996, Vol. 1A, p. 97.

140
HETEROCYCLES, Vol. 64, 2004
2.
(a) K. Ohkata, J. Kimura, Y. Shinohara, R. Takagi, and K. Ohkata, Chem. Commun., 1996, 241. (b)
R. Takagi, J. Kimura, Y. Shinohara, Y. Ohba, K. Takezono, Y. Hiraga, S. Kojima, and K. Ohkata, J.
Chem. Soc., Perkin Trans. 1, 1998, 689. (c) Y. Shinohara, Y. Ohba, R. Takagi, S. Kojima, and K.
Ohkata, Heterocycles, 2001, 55, 9. (d) R. Takagi, M. Nakamura, M. Hashizume, and K. Ohkata,
Tetrahedron Lett., 2001, 42, 5891. (e) R. Takagi, M. Hashizume, M. Nakamura, S. Begum, Y.
Hiraga, S. Kojima, and K. Ohkata, J. Chem. Soc., Perkin Trans. 1, 2002, 179. (f) S. Begum, M. M.
Rahman, R. Takagi, and K. Ohkata, Heterocycles, 2004, 62, 251.
3
.
.
S. Juliá, J. Masana, and J. C. Vega, Angew. Chem., Int. Ed. Engl., 1980, 19, 929.
4
(a) P. A. Bentley, S. Bergeron, M. W. Cappi, D. E. Hibbs, M. H. Hursthouse, T. C. Nugent, R.
Pulido, S. M. Roberts, and L. E. Wu, Chem. Commun., 1997, 739. (b) B. M. Ader, J. V. Barkley, S.
Bergeron, M. W. Cappi, B. E. Flowerdew, M. P. Jackson, R. McCague, T. C. Nugent, and S. M.
Roberts, J. Chem. Soc., Perkin Trans. 1, 1997, 3501. (c) J. V. Allen, S. Bergeron, M. J. Griffiths, S.
Mukherjee, S. M. Roberts, N. M. Williamson, M. Natalie, and L. E. Wu, J. Chem. Soc., Perkin
Trans. 1, 1998, 3171. (d) W.-P. Chen, L. Ann, M. B. Egar, K. M. Hursthouse, M. Abdul, J. E.
Mathews, and S. M. Roberts, Tetrahedron Lett., 1998, 39, 8495. (e) T. Geller and S. M. Roberts, J.
Chem. Soc., Perkin Trans. 1, 1999, 1397.
5.
(a) M. E. Lasterra-Sánchez and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1995, 1467. (b) W.
Kroutil, P. Mayon, M. E. Lasterra-Sánchez, S. J. Maddrell, S. M. Roberts, S. R. Thornton, C. J. Todd,
and M. Tüter, Chem. Commun., 1996, 845. (c) J. V. Allen, M. W. Cappi, P. D. Kary, S. M. Roberts,
N. M. Williamson, and L. E. Wu, Chem. Commun., 1997, 3297.
6
.
.
P. A. Benuley, W. Kroutil, J. A. Littlechild, and S. M. Roberts, Chirality, 1997, 9, 198.
(a) R. Takagi, A. Shiraki, T. Manabe, S. Kojima, and K. Ohkata, Chem. Lett., 2000, 366. (b) R. W.
Flood, T. P. Geller, S. A. Petty, S. M. Roberts, J. Skidmore, and M. Volk, Org. Lett., 2001, 3, 683.
R. Tagkagi, T. Manabe, A. Shiraki, A. Yonesige, Y. Hiraga, S. Kojima, and K. Ohkata, Bull. Chem.
Soc. Jpn, 2000, 73, 2115.
7
8
9
1
.
.
P. A. Bentlry, M. W. Cappi, R. W. Flood, S. M. Roberts, and J. A. Smith, Tetrahedron Lett.,, 1998,
39, 9297.
0. (a) L. A. A. Sluyterman and B. Labruyére, Recl. Trav. Chim. Pays-Bas., 1954, 73, 347. (b) Y.
Iwakura, K. Uni, and M. Oya, J. Polym. Sci. A., 1968, 6, 2165. (c) H. Fukushima and S. Inoue
Makromol. Chem., 1976, 177, 2617.
11. (a) T. Miyazawa and E. J. Blout, J. Am. Chem. Soc., 1961, 83, 712. (b) D. F. Kennedy, M. Crisma, C.
Toniolo, and D. Chapman, Biochemistry, 1991, 30, 6541.
1
2. M. Palumbo, S. DaRiu, G. M. Bonora, and C. Tomiolo, Makromol. Chem., 1976, 177, 1477.
3. D. Konopińska and Z. Siemion, Angew. Chem., Int. Ed. Engl., 1967, 6, 248.
1

HETEROCYCLES, Vol. 64, 2004
141
14. S. Marmor, J. Org. Chem., 1963, 28, 250.
1
5. G. Kumaraswamy, M. N. V. Sastry, Nivedita Jena, K. Ravi Kumar, and M. Vairamani, Tetrahedron
Asymmetry, 2003, 14, 3797.
16. F. G. Weber, H. Glese, H. Koeppel, M. Reinhold, R. Strobe, R. Radeglia, and W. Storek, J. Prakt.
Chem., 1985, 133, 327.
17. P. Hallet, J. Muzart, and J.-P. Pett, J. Org. Chem., 1981, 46, 4275.
18. D. J. Dewar and R. G. Sutherland, J. Chem. Soc., Perkin Trans. 2, 1977, 307.
19. S. Juliá, J. Gulixer, J. Masana, J. Rocas, S. Colonna, R. Annuziata, and H. Molinari, J. Chem. Soc.,
Perkin Trans. 1, 1982, 1317.
2
2
2
2
0. P. Bakaó, E. Czinego, T. Bakó, M. Czulger, and L. Töke, Tetrahedron: Asymmetry, 1999, 10, 4539.
1. F. Toda, H. Takumi, M. Nagami, and K. Tanaka, Heterocycles, 1998, 47, 469.
2. B. Lygo and P. G. Wainwright, Tetrahedron, 1999, 55, 6289.
3. J. Grimshow and D. Mannus, J. Chem. Soc., Perkin Trans. 1, 1977, 2096.