Catalytic asymmetric synthesis of isoxazoline-n-oxides through conjugate additioncyclization under phase-transfer conditions

Article abstract of DOI:10.1246/bcsj.20110155

Catalytic asymmetric synthesis of various isoxazoline-N-oxides having a tetrasubstituted carbon has been accomplished by asymmetric phase-transfer conjugate addition of bromomalonate to nitroolefins and subsequent ringclosing O-alkylation. The obtained isoxazoline-N-oxide was readily converted to the corresponding oxime, isoxazoline, and lactam without loss of optical purity.

Full text of DOI:10.1246/bcsj.20110155

© 2011 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 84, No. 10, 1057-1065 (2011) 1057
Selected Papers
Catalytic Asymmetric Synthesis of Isoxazoline-N-oxides through
Conjugate Addition-Cyclization under Phase-Transfer Conditions
Taichi Kano, Akihiro Yamamoto, Sunhwa Song, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502
Received May 27, 2011; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Catalytic asymmetric synthesis of various isoxazoline-N-oxides having a tetrasubstituted carbon has been
accomplished by asymmetric phase-transfer conjugate addition of bromomalonate to nitroolefins and subsequent ring-
closing O-alkylation. The obtained isoxazoline-N-oxide was readily converted to the corresponding oxime, isoxazoline,
and lactam without loss of optical purity.
Isoxazoline-N-oxides are the synthetic equivalent of isoxa-
zoline, and serve as versatile building blocks for complex
Results and Discussion
molecules,1 biologically active compounds and natural prod-
ucts.2 While a number of synthetic methods have been
developed to date,3 there is still a need to expand synthetic
approaches for their preparation. For instance, chiral isoxa-
zoline-N-oxides are known to be synthesized by using optically
pure starting material4 or stoichiometric amounts of a chiral
reagent;5 however, general methods for their preparation based
on catalytic asymmetric reaction are quite rare.6 In this context,
we have been interested in the development of a catalytic
asymmetric synthesis of chiral isoxazoline-N-oxides under
phase-transfer conditions.7,8 The asymmetric conjugate addi-
tion of bromomalonate to nitroolefins 1 promoted by a chiral
phase-transfer catalyst would give optically enriched nitronates
2, which could be immediately converted to isoxazoline-N-
oxides 3 by an intramolecular O-alkylation (Scheme 1). Here
we wish to report the efficient asymmetric synthesis of
isoxazoline-N-oxides based on the asymmetric phase-transfer
conjugate addition.
We first examined the synthesis of isoxazoline-N-oxides by
the reaction between dialkyl bromomalonate and 1-phenyl-2-
nitropropene (1a) using 1 mol % of (R,R)-4a9 (Chart 1) as
catalyst and K2CO3 in THF (Table 1). Attempted reaction of
dimethyl bromomalonate and 1a gave the desired isoxazoline-
N-oxide in 68% yield with 56% ee (Entry 1). While use of
diethyl bromomalonate improved the yield, a similar level of
enantioselectivity was observed (Entry 2). A sterically more
hindered diisopropyl bromomalonate was not as effective as
asymmetric PTC
conjugate addition
BrCH(CO2R3)2
+
R3O2C Br O
R3O2C
N O
R2
NO2
R1
R1
2
R2
1
intramolecular
O-alkylation
R3O2C
R3O2C
O
O
N
R1
R2
3
Scheme 1. Asymmetric synthesis of isoxazoline-N-oxides by
asymmetric phase-transfer conjugate addition and intra-
molecular O-alkylation.
Chart 1.
Published on the web October 6, 2011; doi:10.1246/bcsj.20110155

1058 Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011)
Asymmetric Synthesis of Isoxazoline-N-oxides
Table 1. Asymmetric Synthesis of Isoxazoline-N-oxide with
1a and Dialkyl Bromomalonate Catalyzed by (R,R)-4aa)
Table 3. Asymmetric Synthesis of Isoxazoline-N-oxide with
1a and Diethyl Bromomalonate Catalyzed by (R,R)-4aa)
Conditions
Yield Ee
Entry
R
Time/h
Yield/%b)
Ee/%c)
Entry Base
Solvent
/%b) /%c)
Temp/°C Time/h
1
2
3
4
Me
Et
i-Pr
Bn
24
7.5
24
24
68
95
74
84
56
58
42
56
1
2
3
4
5
6
7
8
9
K2CO3
50% K2CO3 aq. Et2O
THF
0
0
0
0
0
0
0
0
7.5
8.5
12
11
15
24
7.5
7.5
24
95
84
88
70
71
79
94
83
80
70
97
95
29
58
63
65
67
59
54
64
70
77
79
81
83
77
50% K2CO3 aq. CPME
50% K2CO3 aq. TBME
50% K2CO3 aq. anisole
50% K2CO3 aq. PhCl
50% K2CO3 aq. toluene
50% K2CO3 aq. mesitylene
a) The reaction of 1a (1 equiv) with dialkyl bromomalonate
(1 equiv) was carried out in THF in the presence of (R,R)-4a
(0.01 equiv) and K2CO3 (2 equiv) at 0 °C. b) Isolated yield.
c) Determined by HPLC analysis using chiral column
(Chiralpak AD-H, Daicel Chemical Industries, Ltd.).
50% K2CO3 aq. mesitylene ¹20
10 70% Cs2CO3 aq. mesitylene ¹20
11 70% Cs2CO3 aq. mesitylene ¹30
12 70% Cs2CO3 aq. mesitylene ¹35
13 70% Cs2CO3 aq. mesitylene ¹40
2
8
12
12
Table 2. Asymmetric Synthesis of Isoxazoline-N-oxide with
1a and Diethyl Bromomalonate Catalyzed by Chiral PTC 4a)
a) The reaction of 1a (1 equiv) with diethyl bromomalonate
(1 equiv) was carried out in a solvent in the presence of (R,R)-
4a (0.01 equiv) and a base. b) Isolated yield. c) Determined by
HPLC analysis using chiral column (Chiralpak AD-H, Daicel
Chemical Industries, Ltd.).
Entry
PTC
Yield/%b)
Ee/%c)
Config
1d)
2
3
4
5
6
7
8
(R,R)-4a
(S,S)-4b
(S,S)-4c
(S,S)-4d
(S)-4e
(S,S)-4f
(S,S)-4g
(S,S)-4h
(S,S)-4i
(S,S)-4j
(S,S)-4k
95
87
92
73
76
65
61
55
72
59
48
58
46
56
30
0
47
43
17
47
36
36
S
R
R
R
®
R
R
R
R
R
R
base successfully increased the reaction rate without loss of
enantioselectivity (Entry 10). When the reaction was per-
formed at ¹35 °C for 12 h, the desired product was obtained in
excellent yield with good enantioselectivity (Entry 12).
With the optimal reaction conditions, the catalytic asym-
metric synthesis of isoxazoline-N-oxides with several other
nitroolefins 1 was examined (Table 4). The reaction of nitro-
olefin 1 having a primary alkyl group (R2 = Et or Bu) at the
¡-position gave the corresponding isoxazoline-N-oxide with
good enantioselectivity (Entries 2 and 3). On the other hand,
the reaction of sterically demanding nitroolefin 1 (R2 = i-Pr)
proceeded slowly to give the product in lower yield and
enantioselectivity (Entry 4). We then investigated the effects of
the ¢-substituent on nitroolefin 1. The reaction of 1 having
either electron-deficient or electron-rich phenyl group gave the
corresponding isoxazolines in good yield and enantioselectivity
(Entries 6-8). Use of 1 with heteroaromatic or alkyl substituent
resulted in decreased enantioselectivity (Entries 9-11). Inter-
estingly, the reaction of nitroolefin 1 having an ethoxycarbonyl
group at the ¢-position did not provide the isoxazoline-N-
oxide, giving a considerable amount of oxime epoxide 5 in
racemic form (Entry 12). A possible reaction pathway for the
formation of 5 is shown in Scheme 2.
9
10
11
a) The reaction of 1a (1 equiv) with diethyl bromomalonate
(1 equiv) was carried out in THF in the presence of chiral PTC
4 (0.01 equiv) and K2CO3 (2 equiv) at 0 °C for 24 h. b) Isolated
yield. c) Determined by HPLC analysis using chiral column
(Chiralpak AD-H, Daicel Chemical Industries, Ltd.). d) The
reaction was performed for 7.5 h.
other primary alkyl esters in terms of both yield and
enantioselectivity (Entry 3). Accordingly, diethyl bromomalo-
nate was chosen for further investigation. Intensive catalyst
screening revealed that (R,R)-4a was the most efficient catalyst
for the present reaction (Table 2).
Having identified a suitable catalyst, solvent screening was
then carried out (Table 3). Among ethereal solvents used, a less
polar solvent such as t-butyl methyl ether (TBME) showed
higher enantioselectivity (Entry 4). We then screened a variety
of aromatic solvents (Entries 5-8), and mesitylene was found to
be a suitable solvent in terms of enantioselectivity (Entry 8). In
an attempt to further improve enantioselectivity, lowering
temperature was effective, although a longer reaction time was
required (Entry 9). Use of 70% aqueous Cs2CO3 as a stronger
The absolute stereochemistry of the obtained isoxazoline-N-
oxide (Table 4, Entry 6) was confirmed to be S by X-ray
crystallographic analysis (Figure 1). Based on the observed
stereochemistry, a plausible transition state model can be
proposed as shown in Figure 2. The chiral ammonium enolate,
which is generated from diethyl bromomalonate and chiral
phase-transfer catalyst (R,R)-4a under basic conditions, ap-
proaches the Si face of nitroolefin.

T. Kano et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011) 1059
Table 4. Asymmetric Synthesis of Isoxazoline-N-oxide with
1 and Diethyl Bromomalonate Catalyzed by (R,R)-4aa)
Entry
R1
R2
Yield/%b)
Ee/%c),d)
1
2
3
Ph
Ph
Ph
Ph
Me
Et
Bu
i-Pr
Ph
Et
Et
Et
Et
Et
95
92
56
63
97
84
90
84
85
36
63
73g)
83 (99)
86
86
EtO2C
EtO2C
4e)
5
77
O
O
N
Ph
81 (99)
85 (97)
87
87
78
72
77
®
6e)
7
4-Br-C6H4
4-NO2-C6H4
4-MeO-C6H4
2-furyl
3-pyridyl
Bu
Et
8f)
9e)
10
11
12
Br
Figure 1. X-ray structure of isoxazoline-N-oxide.
Et
Et
CO2Et
a) The reaction of 1 (1 equiv) with diethyl bromomalonate
(1 equiv) was carried out in mesitylene in the presence of
(R,R)-4a (0.01 equiv) and 70% Cs2CO3 aq. at ¹35 °C for 12 h.
b) Isolated yield. c) Determined by HPLC analysis using chiral
column (Chiralpak AD-H or Chiralcel OD-H, Daicel Chemical
Industries, Ltd.). d) Enantiomeric excesses in parentheses were
obtained after a single recrystallization from cold ethanol.
e) The reaction was performed for 24 h. f) The reaction was
performed for 36 h. g) Oxime epoxide 5 was obtained instead
of the expected isoxazoline-N-oxide.
Figure 2. Plausible transition state model.
OH
EtO2C
EtO2C
O
OH
N
O
Pd/C, H2
MeOH, rt
MsCl, Et3N
N
EtO2C
EtO2C
Et
CH2Cl2, 0 °C~rt
Ph
Et
Ph
7 (86% ee)
6 (86% ee)
93%
93%
EtO2C
EtO2C
HO
EtO2C
O
O
LiAlH(t-OBu)3
THF, 0 °C~rt
BnBr, Ag2O
DMF, rt
N
N
Ph
8 (86% ee)
Et
Ph
Et
87% (dr = >20:1) 9 (85% ee)
94%
O
HO
BnO
BnO
EtO2C
O
NiCl2·6H2O, NaBH4
N
NH
Et
MeOH-THF, –40 °C
Ph
Et
Ph
10 (85% ee)
93% (dr = >20:1)
11 (85% ee)
Scheme 3. Transformation of isoxazoline-N-oxide 6.
exclusively.11 The O-benzylation of 9 afforded benzyl ether 10,
which was then converted to lactam 11 through diastereo-
selective reduction of the C=N bond,6 the N-O bond cleavage
and lactamization. The relative stereochemistry of 9 and 11 was
determined by X-ray crystallographic analysis as shown in
Figure 3 and Figure 4, respectively.
Scheme 2. A possible reaction pathway for the formation of
oxime epoxide 5.
The obtained isoxazoline-N-oxide was a useful intermediate
in organic synthesis and readily converted to the corresponding
oxime, isoxazoline, and lactam (Scheme 3). When isoxazoline-
N-oxide 6 was treated with Pd/C in MeOH under H2
atmosphere, oxime 7 was obtained in excellent yield with
complete retention of stereochemistry. Treatment of 7 with
methanesulfonyl chloride and triethylamine in dichloromethane
gave isoxazoline 8 in excellent yield without loss of optical
purity.10 Selective reduction of one ester group in 8 with
lithium tri(t-butoxy)aluminium hydride gave mono-alcohol 9
Conclusion
In summary, we have developed an efficient asymmetric
synthesis of isoxazoline-N-oxides by asymmetric phase-trans-
fer conjugate addition and subsequent ring-closing O-alkyla-
tion. The obtained isoxazoline-N-oxide was readily converted
to useful building blocks in organic synthesis such as the
corresponding oxime, isoxazoline, and lactam.

1060 Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011)
Asymmetric Synthesis of Isoxazoline-N-oxides
cartridges (10 g). In experiments requiring dry solvent, tetra-
hydrofuran (THF) and CH2Cl2 were purchased from Kanto
Chemical Co., Inc. as “Dehydrated.” Commercially available
reagents were used as received. Nitroolefins12-16 and phase-
transfer catalysts (R,R)-4a,9 (S,S)-4b,17 (S,S)-4c,17 (S,S)-4d,17
(S)-4e,18 (S,S)-4f,17 (S,S)-4g,19 (S,S)-4h,20 (S,S)-4i,20 (S,S)-4j,20
and (S,S)-4k20 were synthesized according to literature proce-
dures and used after column chromatography on silica gel.
General Procedure for Asymmetric Synthesis of Isoxazo-
line-N-oxides with 1-Phenyl-2-nitropropene (1a) and Dial-
kyl Bromomalonates. To a suspension of (R,R)-4a (2.2 mg,
0.0025 mmol), 1-phenyl-2-nitropropene (1a) (40.8 mg, 0.25
mmol) and dialkyl bromomalonate (0.25 mmol) in THF
(0.33 mL) at 0 °C was added K2CO3 (69.1 mg, 0.5 mmol).
After stirring for 24 h at 0 °C, the reaction mixture was
quenched with saturated NH4Cl solution, and extracted with
ethyl acetate. The organic layer was washed with brine, dried
over Na2SO4, and concentrated. The resulting residue was
purified by flash column chromatography on silica gel to give
the corresponding cyclic nitronate. The product was identified
by NMR spectroscopy. The enantiomeric excess of the product
was determined by HPLC using a chiral column.
Figure 3. X-ray structure of isoxazoline 9.
Dimethyl (S)-3-Methyl-4-phenyl-4,5-dihydroisoxazole-
20
5,5-dicarboxylate 2-Oxide (Table 1, Entry 1): ½¡ꢀD 1.55
1
(c 1.0, CHCl3; 56% ee); H NMR (300 MHz, CDCl3): ¤ 7.43-
7.33 (3H, m, Ar-H), 7.27-7.19 (2H, m, Ar-H), 5.29 (1H, d,
J = 1.5 Hz, Ar-CH), 3.89 (3H, s, -CO2CH3), 3.26 (3H, s,
-CO2CH3), 1.92 (3H, d, J = 1.5 Hz, -C(=N)CH3); 13C NMR
(75 MHz, CDCl3): ¤ 166.6, 164.2, 132.7, 129.1, 128.9, 128.8,
112.7, 84.4, 57.1, 54.0, 52.7, 11.1; IR (neat): 2956, 1752, 1665,
1454, 1390, 1335, 1277, 1212, 1094, 1045 cm¹1; HRMS (ESI):
Calcd for C14H16NO6: 294.0978 ([M + H]+), Found: 294.0972
([M + H]+); HPLC analysis: Daicel Chiralpak AD-H, 254 nm,
hexane/2-propanol = 9:1, flow rate 1.0 mL min¹1, retention
time: 11.3 (R) and 14.5 min (S).
Figure 4. X-ray structure of lactam 11.
Experimental
Diisopropoxyl (S)-3-Methyl-4-phenyl-4,5-dihydroisoxa-
20
Infrared (IR) spectra were recorded on
a
Nicolet
zole-5,5-dicarboxylate 2-Oxide (Table 1, Entry 3): ½¡ꢀD
1
MAGNA560. 1H NMR spectra were measured on Bruker
AV500 (500 MHz) and Bruker AV300 (300 MHz) spectrome-
ters. Data were reported as follows: chemical shifts in ppm
from tetramethylsilane (in the case of CDCl3) as an internal
standard, integration, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, dd = double-doublet, m = multiplet,
br = broad, and app = apparent), coupling constants (Hz), and
assignment. 13C NMR spectra were measured on Bruker AV500
(125 MHz) and Bruker AV300 (75 MHz) spectrometer with
complete proton decoupling. Chemical shifts were reported in
ppm from the residual solvent as an internal standard. High-
performance liquid chromatography (HPLC) was performed on
Shimadzu 10A instruments using Daicel Chiralpak AD-H and
Chiralcel OD-H 4.6 mm © 25 cm columns. High-resolution
mass spectra (HRMS) were performed on a Thermo Fisher
Scientific LTQ Orbitrap XL and a JEOL JMS-700 MStation.
Optical rotations were measured on a JASCO P-1020 digital
polarimeter. For thin layer chromatography (TLC) analysis
throughout this work, Merck precoated TLC plates (silica gel
60 GF254, 0.25 mm) were used. Flash column chromatography
was performed with silica gel 60 (Merck 1.09386.9025, 230-
400 mesh) or using a Biotage Isolera with prepacked silica
1.00 (c 1.0, CHCl3; 42% ee); H NMR (300 MHz, CDCl3): ¤
7.40-7.31 (3H, m, Ar-H), 7.30-7.20 (2H, m, Ar-H), 5.25 (1H,
d, J = 1.4 Hz, Ar-CH), 5.19-5.11 (1H, m, -CO2CH(CH3)2),
4.64-4.56 (1H, m, -CO2CH(CH3)2), 1.88 (3H, d, J = 1.4 Hz,
-C(=N)CH3), 1.33 (3H, d, J = 6.3 Hz, -CO2CH(CH3)2), 1.27
(3H, d, J = 6.2 Hz, -CO2CH(CH3)2), 0.99 (3H, d, J = 6.3 Hz,
-CO2CH(CH3)2), 0.64 (3H, d, J = 6.2 Hz, -CO2CH(CH3)2);
13C NMR (75 MHz, CDCl3): ¤ 165.7, 163.3, 133.1, 129.3,
129.0, 128.9, 113.5, 84.2, 71.4, 70.5, 56.6, 21.4, 21.24, 21.17,
20.6, 11.1; IR (neat): 2983, 2936, 1742, 1665, 1377, 1277,
¹1
1211, 1102 cm
; HRMS (ESI): Calcd for C18H24NO6:
350.1604 ([M + H]+), Found: 350.1585 ([M + H]+); HPLC
analysis: Daicel Chiralpak AD-H, 254 nm, hexane/2-propa-
nol = 9:1, flow rate 1.0 mL min¹1, retention time: 16.6 (R) and
20.7 min (S).
Dibenzyl
(S)-3-Methyl-4-phenyl-4,5-dihydroisoxazole-
20
5,5-dicarboxylate 2-Oxide (Table 1, Entry 4): ½¡ꢀD 0.97
1
(c 1.0, CHCl3; 56% ee); H NMR (300 MHz, CDCl3): ¤ 7.40-
7.14 (13H, m, Ar-H), 6.94-6.87 (2H, m, Ar-H), 5.32 (1H, d,
J = 12.2 Hz, -CO2CH2Ph), 5.26 (1H, d, J = 1.4 Hz, Ar-CH),
5.16 (1H, d, J = 12.2 Hz, -CO2CH2Ph), 4.67 (1H, d, J =
12.2 Hz, -CO2CH2Ph), 4.42 (1H, d, J = 12.2 Hz, -CO2CH2Ph),

T. Kano et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011) 1061
1.88 (3H, d, J = 1.4 Hz, -C(=N)CH3); 13C NMR (75 MHz,
CDCl3): ¤ 166.0, 163.6, 134.3, 133.7, 132.6, 129.2, 129.0,
128.9, 128.6 (two peaks overlap), 128.5, 128.4, 128.3, 128.1,
Diethyl (S)-3-Butyl-4-phenyl-4,5-dihydroisoxazole-5,5-di-
carboxylate 2-Oxide (Table 4, Entry 3): ½¡ꢀD 2.15 (c 1.0,
20
CHCl3; 86% ee); 1H NMR (300 MHz, CDCl3): ¤ 7.39-7.32
(3H, m, Ar-H), 7.28-7.22 (2H, m, Ar-H), 5.26 (1H, s,
Ar-CH), 4.38 (1H, dq, J = 10.7, 7.1 Hz, -CO2CH2CH3),
4.29 (1H, dq, J = 10.7, 7.2 Hz, -CO2CH2CH3), 3.78 (1H,
dq, J = 10.7, 7.2 Hz, -CO2CH2CH3), 3.68 (1H, dq, J =
10.7, 7.2 Hz, -CO2CH2CH3), 2.45 (1H, dt, J = 15.1,
7.5 Hz, -C(=N)CH2CH2), 2.05 (1H, dt, J = 14.3, 7.1 Hz,
-C(=N)CH2CH2), 1.50-1.22 (4H, m, -C(=N)CH2(CH2)2CH3),
1.31 (3H, t, J = 7.1 Hz, -CO2CH2CH3), 0.854 (3H, t,
J = 7.2 Hz, -C(=N)(CH2)3CH3), 0.846 (3H, t, J = 7.1 Hz,
-CO2CH2CH3); 13C NMR (75 MHz, CDCl3): ¤ 166.4, 163.8,
133.2, 129.13, 129.07, 128.8, 116.9, 84.5, 63.3, 62.3, 56.0,
27.0, 25.2, 22.2, 13.8, 13.5, 13.4; IR (neat): 2961, 2934, 1746,
1653, 1457, 1369, 1278, 1208, 1095, 1041 cm¹1; HRMS (ESI):
Calcd for C19H26NO6: 364.1752 ([M + H]+), Found: 364.1755
([M + H]+); HPLC analysis: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol = 20:1, flow rate 1.0 mL min¹1, retention
time: 22.6 (S) and 26.8 min (R).
113.0, 84.5, 68.8, 67.9, 57.0, 11.1; IR (neat): 3064, 3033, 2957,
¹1
1746, 1665, 1498, 1454, 1378, 1334, 1276, 1202, 1089 cm
;
HRMS (ESI): Calcd for C26H24NO6: 446.1604 ([M + H]+),
Found: 446.1626 ([M + H]+); HPLC analysis: Daicel
Chiralpak AD-H, 254 nm, hexane/EtOH = 4:1, flow rate
1.0 mL min¹1, retention time: 17.9 (R) and 19.3 min (S).
General Procedure for Asymmetric Synthesis of Isoxazo-
line-N-oxides with Nitroolefin 1 and Diethyl Bromomalo-
nate.
To a suspension of (R,R)-4a (0.9 mg, 0.001 mmol),
diethyl bromomalonate (23.9 mg, 0.1 mmol) and nitroolefin
(0.1 mmol) in mesitylene (0.33 mL) at ¹35 °C was added 70%
Cs2CO3 solution (0.12 mL). After stirring for 12 h at ¹35 °C,
the reaction mixture was quenched with saturated NH4Cl
solution, and extracted with ethyl acetate. The organic layer
was washed with brine, dried over Na2SO4, and concentrated.
The resulting residue was purified by flash column chromatog-
raphy on silica gel to give the corresponding cyclic nitronate.
The product was identified by NMR spectroscopy. The
enantiomeric excess of the product was determined by HPLC
using a chiral column.
Diethyl (S)-3-Isopropyl-4-phenyl-4,5-dihydroisoxazole-
20
5,5-dicarboxylate 2-Oxide (Table 4, Entry 4): ½¡ꢀD 2.21
1
(c 1.0, CHCl3; 77% ee); H NMR (300 MHz, CDCl3): ¤ 7.37-
Diethyl (S)-3-Methyl-4-phenyl-4,5-dihydroisoxazole-5,5-
7.26 (5H, m, Ar-H), 5.15 (1H, s, Ar-CH), 4.38 (1H, dq,
J = 10.6, 7.2 Hz, -CO2CH2CH3), 4.28 (1H, dq, J = 10.6,
7.1 Hz, -CO2CH2CH3), 3.79 (1H, dq, J = 11.1, 7.0 Hz,
-CO2CH2CH3), 3.72 (1H, dq, J = 11.0, 6.9 Hz, -CO2CH2CH3),
2.81 (1H, m, -C(=N)CH(CH3)2), 1.31 (3H, t, J = 7.1 Hz,
-CO2CH2CH3), 1.15 (3H, d, J = 7.0 Hz, -C(=N)CH(CH3)2),
0.88 (3H, d, J = 7.0 Hz, -C(=N)CH(CH3)2), 0.85 (3H, t,
J = 7.0 Hz, -CO2CH2CH3); 13C NMR (75 MHz, CDCl3): ¤
166.6, 163.6, 133.9, 129.2, 129.1, 128.8, 120.9, 84.9, 63.4,
62.3, 55.3, 27.0, 18.5, 18.1, 13.9, 13.4; IR (neat): 2978, 2938,
1747, 1651, 1457, 1369, 1247, 1087, 1038 cm¹1; HRMS (ESI):
Calcd for C18H24NO6: 350.1597 ([M + H]+), Found: 350.1598
([M + H]+); HPLC analysis: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol = 9:1, flow rate 0.5 mL min¹1, retention
time: 13.5 (S) and 12.1 min (S).
20
dicarboxylate 2-Oxide (Table 4, Entry 1):
½¡ꢀD 2.28
1
(c 1.0, CHCl3; 83% ee); H NMR (300 MHz, CDCl3): ¤ 7.39-
7.32 (3H, m, Ar-H), 7.27-7.19 (2H, m, Ar-H), 5.27 (1H, s, Ar-
CH), 4.38 (1H, dq, J = 11.1, 7.3 Hz, -CO2CH2CH3), 4.30 (1H,
dq, J = 11.1, 7.3 Hz, -CO2CH2CH3), 3.78 (1H, dq, J = 10.7,
7.2 Hz, -CO2CH2CH3), 3.66 (1H, dq, J = 10.7, 7.2 Hz,
-CO2CH2CH3), 1.90 (3H, d, J = 1.4 Hz, -C(=N)CH3), 1.31
(3H, t, J = 7.1 Hz, -CO2CH2CH3), 0.84 (3H, t, J = 7.1 Hz,
-CO2CH2CH3); 13C NMR (75 MHz, CDCl3): ¤ 166.3, 163.8,
133.0, 129.14, 129.09, 128.9, 113.1, 84.4, 63.4, 62.3, 56.9,
13.8, 13.4, 11.1; IR (neat): 2984, 1747, 1664, 1457, 1369,
1262, 1208, 1095, 1045 cm¹1; HRMS (ESI): Calcd for
C16H20NO6: 322.1284 ([M + H]+), Found: 322.1285
([M + H]+); HPLC analysis: Daicel Chiralpak AD-H,
¹1
254 nm, hexane/2-propanol = 9:1, flow rate 1.0 mL min
retention time: 10.7 (R) and 12.1 min (S).
,
Diethyl (S)-3,4-Diphenyl-4,5-dihydroisoxazole-5,5-dicar-
20
boxylate 2-Oxide (Table 4, Entry 5): ½¡ꢀD 2.51 (c 1.0,
Diethyl (S)-3-Ethyl-4-phenyl-4,5-dihydroisoxazole-5,5-di-
CHCl3; 81% ee); 1H NMR (300 MHz, CDCl3): ¤ 7.86-7.76
(2H, m, Ar-H), 7.36-7.24 (8H, m, Ar-H), 5.76 (1H, s, Ar-CH),
4.40 (1H, dq, J = 10.7, 7.1 Hz, -CO2CH2CH3), 4.31 (1H,
dq, J = 10.7, 7.1 Hz, -CO2CH2CH3), 3.80 (1H, dq, J =
10.8, 7.2 Hz, -CO2CH2CH3), 3.72 (1H, dq, J = 10.7, 7.2 Hz,
-CO2CH2CH3), 1.32 (3H, t, J = 7.1 Hz, -CO2CH2CH3), 0.90
(3H, t, J = 7.1 Hz, -CO2CH2CH3); 13C NMR (75 MHz,
CDCl3): ¤ 166.5, 163.5, 133.9, 129.7, 129.1, 129.0, 128.9,
128.7, 126.9, 125.0, 115.4, 84.8, 63.5, 62.5, 55.4, 13.8, 13.4;
IR (neat): 2983, 1747, 1626, 1494, 1448, 1370, 1298, 1233,
1094, 1061, 1041 cm¹1; HRMS (ESI): Calcd for C21H22NO6:
384.1440 ([M + H]+), Found: 384.1442 ([M + H]+); HPLC
analysis: Daicel Chiralpak AD-H, 254 nm, hexane/EtOH =
4:1, flow rate 0.5 mL min¹1, retention time: 19.1 (S) and
24.3 min (R).
20
carboxylate 2-Oxide (6) (Table 4, Entry 2): ½¡ꢀD 2.58 (c
1.0, CHCl3; 86% ee); 1H NMR (300 MHz, CDCl3): ¤ 7.39-7.32
(3H, m, Ar-H), 7.28-7.22 (2H, m, Ar-H), 5.26 (1H, s, Ar-CH),
4.39 (1H, dq, J = 10.7, 7.1 Hz, -CO2CH2CH3), 4.29 (1H, dq,
J = 10.7, 7.2 Hz, -CO2CH2CH3), 3.78 (1H, dq, J = 10.7,
7.2 Hz, -CO2CH2CH3), 3.68 (1H, dq, J = 10.7, 7.2 Hz,
-CO2CH2CH3), 2.49 (1H, dqd, J = 15.3, 7.6, 0.9 Hz,
-C(=N)CH2CH3), 2.15 (1H, dqd, J = 15.3, 7.6, 1.3 Hz,
-C(=N)CH2CH3), 1.32 (3H, t, J = 7.2 Hz, -CO2CH2CH3),
1.02 (3H, t, J = 7.6 Hz, -C(=N)CH2CH3), 0.84 (3H, t,
J = 7.2 Hz, -CO2CH2CH3); 13C NMR (75 MHz, CDCl3): ¤
166.4, 163.8, 133.2, 129.2, 129.1, 128.9, 117.6, 84.5, 63.4,
62.3, 55.8, 19.2, 13.8, 13.4, 9.3; IR (neat): 2982, 1746, 1654,
1457, 1368, 1279, 1227, 1205, 1093, 1039 cm¹1; HRMS (ESI):
Calcd for C17H22NO6: 336.1440 ([M + H]+), Found: 336.1442
([M + H]+); HPLC analysis: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol = 9:1, flow rate 0.5 mL min¹1, retention
time: 17.2 (S) and 20.2 min (R).
Diethyl (S)-4-(4-Bromophenyl)-3-ethyl-4,5-dihydroisoxa-
20
zole-5,5-dicarboxylate 2-Oxide (Table 4, Entry 6): ½¡ꢀD
1
2.12 (c 1.0, CHCl3; 85% ee); H NMR (300 MHz, CDCl3): ¤
7.50 (2H, dd, J = 8.5, 2.2 Hz, Ar-H), 7.14 (2H, dd, J = 8.5,

1062 Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011)
Asymmetric Synthesis of Isoxazoline-N-oxides
2.2 Hz, Ar-H), 5.23 (1H, s, Ar-CH), 4.38 (1H, dq, J = 10.7,
7.1 Hz, -CO2CH2CH3), 4.29 (1H, dq, J = 10.7, 7.1 Hz,
-CO2CH2CH3), 3.85 (1H, dq, J = 10.7, 7.2 Hz, -CO2CH2CH3),
3.75 (1H, dq, J = 10.7, 7.1 Hz, -CO2CH2CH3), 2.48 (1H,
dqd, J = 15.2, 7.7, 0.9 Hz, -C(=N)CH2CH3), 2.14 (1H,
dqd, J = 15.3, 7.7, 1.3 Hz, -C(=N)CH2CH3), 1.32 (3H,
t, J = 7.1 Hz, -CO2CH2CH3), 1.02 (3H, t, J = 7.6 Hz,
-C(=N)CH2CH3), 0.92 (3H, t, J = 7.2 Hz, -CO2CH2CH3);
13C NMR (75 MHz, CDCl3): ¤ 166.2, 163.6, 132.3, 132.1,
130.8, 123.4, 116.9, 84.2, 63.5, 62.5, 55.2, 19.1, 13.8, 13.5,
9.3; IR (neat): 2981, 1747, 1654, 1488, 1368, 1280, 1227,
1205, 1093, 1040, 1012 cm¹1; HRMS (ESI): Calcd for
C17H21BrNO6: 414.0546 ([M + H]+), Found: 414.0547
([M + H]+); HPLC analysis: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol = 40:1, flow rate 0.7 mL min¹1, retention
time: 33.2 (R) and 35.5 min (S).
Crystal Structure Analysis of Diethyl (S)-4-(4-Bromo-
phenyl)-3-ethyl-4,5-dihydroisoxazole-5,5-dicarboxylate 2-
Oxide: Single crystals of diethyl (S)-4-(4-bromophenyl)-3-
ethyl-4,5-dihydroisoxazole-5,5-dicarboxylate 2-oxide for X-ray
diffraction experiments were recrystallized from EtOH. The
data were collected at ¹177 °C on a Rigaku R-AXIS RAPID
IP area detector with graphite-monochromated Mo K¡ radia-
tion (- = 0.71075 ¡). The crystal structure was solved by
direct methods using SIR9221 and expanded using DIRDIF99
Fourier techniques.22 The non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were refined isotropically.
The final cycle of full-matrix least-squares refinement23 on F2
was based on 4145 observed reflections and 306 variable
parameters. Crystallographic data for (c): C17H20BrNO6,
colorless block, 0.5 © 0.4 © 0.3 mm3, orthorhombic, P212121,
a = 10.0497(2), b = 10.3362(3), c = 17.5284(5) ¡, V =
1820.77(8) ¡3, Dcalcd = 1.511 g cm¹3, Z = 4, 2ªmax = 55.0°,
® = 22.962 cm¹1. A total of 17820 reflections were measured.
R = 0.024, and Rw = 0.041 for all reflections. All calculations
were performed using the CrystalStructure3.824 crystallograph-
ic software package. CCDC-796797 contains the supplemen-
tary crystallographic data for this paper. Crystallographic data
have been deposited with Cambridge Crystallographic Data
Centre: Deposition number CCDC-796797 for the title com-
pound. Copies of the data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, U.K.; Fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
9.3; IR (neat): 2983, 2941, 1747, 1655, 1607, 1525, 1351,
1279, 1229, 1205, 1095, 1040, 1014 cm¹1; HRMS (ESI): Calcd
for C17H21N2O8: 381.1291 ([M + H]+), Found: 381.1292
([M + H]+); HPLC analysis: Daicel Chiralpak AD-H, 254
nm, hexane/2-propanol = 4:1, flow rate 1.0 mL min¹1, reten-
tion time: 13.1 (S) and 19.2 min (R).
Diethyl
(S)-3-Ethyl-4-(4-methoxyphenyl)-4,5-dihydro-
isoxazole-5,5-dicarboxylate 2-Oxide (Table 4, Entry 8):
20
½¡ꢀD 2.42 (c 1.0, CHCl3; 87% ee); 1H NMR (300 MHz,
CDCl3): ¤ 7.17 (2H, d, J = 8.6 Hz, Ar-H), 6.86 (2H, d,
J = 8.5 Hz, Ar-H), 5.21 (1H, s, Ar-CH), 4.37 (1H, dq,
J = 10.7, 7.1 Hz, -CO2CH2CH3), 4.28 (1H, dq, J = 10.6,
7.1 Hz, -CO2CH2CH3), 3.83 (1H, dq, J = 10.7, 7.1 Hz,
-CO2CH2CH3), 3.80 (3H, s, -OCH3), 3.73 (1H, dq, J =
10.6, 7.2 Hz, -CO2CH2CH3), 2.47 (1H, dq, J = 15.2, 7.6 Hz,
-C(=N)CH2CH3), 2.15 (1H, dq, J = 15.2, 7.6 Hz,
-C(=N)CH2CH3), 1.31 (3H, t, J = 7.1 Hz, -CO2CH2CH3),
1.02 (3H, t, J = 7.6 Hz, -C(=N)CH2CH3), 0.91 (3H, t,
J = 7.1 Hz, -CO2CH2CH3); 13C NMR (75 MHz, CDCl3): ¤
166.5, 163.9, 160.1, 130.4, 124.9, 117.7, 114.2, 84.6, 63.3,
62.3, 55.3, 55.2, 19.2, 13.9, 13.6, 9.3; IR (neat): 2981, 2362,
1747, 1653, 1611, 1514, 1458, 1368, 1252, 1228, 1206, 1179,
¹1
1094, 1036 cm
; HRMS (ESI): Calcd for C18H24NO7:
366.1544 ([M + H]+), Found: 366.1547 ([M + H]+); HPLC
analysis: Daicel Chiralpak AD-H, 254 nm, hexane/2-propa-
nol = 9:1, flow rate 0.8 mL min¹1, retention time: 23.0 (R) and
24.9 min (S).
Diethyl (R)-3-Ethyl-4-(furan-2-yl)-4,5-dihydroisoxazole-
20
5,5-dicarboxylate 2-Oxide (Table 4, Entry 9): ½¡ꢀD 1.91
1
(c 1.0, CHCl3; 78% ee); H NMR (300 MHz, CDCl3): ¤ 7.41
(1H, d, J = 1.3 Hz, Ar-H), 6.38 (2H, app d, J = 1.3 Hz, Ar-H),
5.47 (1H, t, J = 1.2 Hz, Ar-CH), 4.37 (1H, dq, J = 10.7,
7.2 Hz, -CO2CH2CH3), 4.29 (1H, dq, J = 10.8, 7.2 Hz,
-CO2CH2CH3), 4.04 (1H, dq, J = 10.7, 7.2 Hz, -CO2CH2CH3),
3.95 (1H, dq, J = 10.7, 7.2 Hz, -CO2CH2CH3), 2.45 (1H,
dqd, J = 15.2, 7.6, 1.0 Hz, -C(=N)CH2CH3), 2.22 (1H,
dqd, J = 15.2, 7.6, 1.4 Hz, -C(=N)CH2CH3), 1.31 (3H,
t, J = 7.2 Hz, -CO2CH2CH3), 1.07 (3H, t, J = 7.2 Hz,
-CO2CH2CH3), 1.03 (3H, t, J = 7.6 Hz, -C(=N)CH2CH3);
13C NMR (75 MHz, CDCl3): ¤ 165.8, 163.9, 146.1, 143.5,
114.8, 111.1, 111.0, 83.1, 63.5, 62.7, 49.7, 19.1, 13.8, 13.7, 9.0;
IR (neat): 3123, 2984, 2941, 1745, 1659, 1464, 1368, 1301,
1281, 1240, 1208, 1096, 1039, 1013 cm¹1; HRMS (ESI): Calcd
for C15H20NO7: 326.1233 ([M + H]+), Found: 326.1234
([M + H]+); HPLC analysis: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol = 9:1, flow rate 1.0 mL min¹1, retention
time: 9.5 (S) and 12.6 min (R).
Diethyl (S)-3-Ethyl-4-(4-nitrophenyl)-4,5-dihydroisoxa-
20
zole-5,5-dicarboxylate 2-Oxide (Table 4, Entry 7): ½¡ꢀD
1
1.85 (c 1.0, CHCl3; 87% ee); H NMR (300 MHz, CDCl3): ¤
Diethyl
(S)-3-Ethyl-4-(pyridin-3-yl)-4,5-dihydroisoxa-
20
8.24 (2H, dd, J = 8.8, 2.2 Hz, Ar-H), 7.49 (2H, dd, J = 8.8,
2.2 Hz, Ar-H), 5.38 (1H, s, Ar-CH), 4.40 (1H, dq, J = 10.8,
7.1 Hz, -CO2CH2CH3), 4.31 (1H, dq, J = 10.7, 7.1 Hz,
-CO2CH2CH3), 3.85 (1H, dq, J = 10.8, 7.1 Hz, -CO2CH2CH3),
3.75 (1H, dq, J = 10.8, 7.1 Hz, -CO2CH2CH3), 2.51 (1H,
dqd, J = 15.2, 7.7, 0.8 Hz, -C(=N)CH2CH3), 2.14 (1H,
dqd, J = 15.2, 7.7, 1.3 Hz, -C(=N)CH2CH3), 1.33 (3H,
t, J = 7.1 Hz, -CO2CH2CH3), 1.03 (3H, t, J = 7.6 Hz,
-C(=N)CH2CH3), 0.92 (3H, t, J = 7.1 Hz, -CO2CH2CH3);
13C NMR (75 MHz, CDCl3): ¤ 165.9, 163.4, 148.3, 140.7,
130.2, 124.0, 116.3, 84.1, 63.7, 62.7, 55.1, 19.1, 13.8, 13.5,
zole-5,5-dicarboxylate 2-Oxide (Table 4, Entry 10): ½¡ꢀD
1
1.86 (c 1.0, CHCl3; 72% ee); H NMR (300 MHz, CDCl3): ¤
8.62 (1H, dd, J = 4.7, 1.3 Hz, Ar-H), 8.54 (1H, d, J = 1.9 Hz,
Ar-H), 7.62 (1H, ddd, J = 7.9, 1.9, 1.9 Hz, Ar-H), 7.33 (1H,
dd, J = 7.9, 4.8 Hz, Ar-H), 5.30 (1H, s, Ar-CH), 4.40 (1H, dq,
J = 10.8, 7.1 Hz, -CO2CH2CH3), 4.31 (1H, dq, J = 10.7,
7.1 Hz, -CO2CH2CH3), 3.84 (1H, dq, J = 10.9, 7.2 Hz,
-CO2CH2CH3), 3.76 (1H, dq, J = 10.8, 7.1 Hz, -CO2CH2CH3),
2.51 (1H, dq, J = 15.2, 7.6 Hz, -C(=N)CH2CH3), 2.15
(1H, dqd, J = 15.3, 7.7, 1.1 Hz, -C(=N)CH2CH3), 1.33
(3H, t, J = 7.1 Hz, -CO2CH2CH3), 1.04 (3H, t, J = 7.6 Hz,

T. Kano et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011) 1063
-C(=N)CH2CH3), 0.89 (3H, t, J = 7.1 Hz, -CO2CH2CH3);
13C NMR (75 MHz, CDCl3): ¤ 166.0, 163.5, 150.5, 150.3,
136.3, 129.4, 123.7, 116.4, 84.2, 63.6, 62.7, 53.2, 19.1, 13.8,
13.5, 9.4; IR (neat): 2984, 2941, 1747, 1652, 1591, 1577, 1429,
1368, 1278, 1094, 1040 cm¹1; HRMS (ESI): Calcd for
C16H21N2O6: 337.1392 ([M + H]+), Found: 337.1394
169.9, 167.8, 162.3, 134.0, 130.4, 128.3, 128.0, 82.3, 62.5,
62.4, 53.0, 21.5, 14.0, 13.8, 9.8; IR (neat): 3427, 2980, 2366,
¹1
2340, 1741, 1462, 1452, 1367, 1262, 1220, 1149, 1040 cm
;
HRMS (FAB): Calcd for C17H24NO6: 338.1604 ([M + H]+),
Found: 338.1596 ([M + H]+); HPLC analysis: Daicel
Chiralpak AD-H, 230 nm, hexane/2-propanol = 9:1, flow rate
1.0 mL min¹1, retention time: 14.5 (R) and 19.3 min (S).
Diethyl (S)-3-Ethyl-4-phenyl-4,5-dihydroisoxazole-5,5-di-
carboxylate (8). To a solution of 7 (33.7 mg, 0.1 mmol) and
Et3N (21.2 mg, 0.21 mmol) in CH2Cl2 (0.5 mL) was added
MsCl (11.4 mg, 0.1 mmol) dropwise at 0 °C under argon
atmosphere, and the cooling bath was then removed.10 The
reaction mixture was stirred overnight at room temperature and
poured into water. After extraction with ethyl acetate, the
organic layer was washed with brine, dried over Na2SO4, and
concentrated. The resulting residue was purified by flash
column chromatography on silica gel (hexane/ethyl ace-
tate = 5:1 as eluent) to give the title compound 8 (29.8 mg,
([M + H]+); HPLC analysis: Daicel Chiralpak AD-H,
¹1
254 nm, hexane/2-propanol = 4:1, flow rate 1.0 mL min
retention time: 10.9 (R) and 14.8 min (S).
,
Diethyl (S)-4-Butyl-3-ethyl-4,5-dihydroisoxazole-5,5-di-
20
carboxylate 2-Oxide (Table 4, Entry 11):
½¡ꢀD 1.55 (c
1.0, CHCl3; 77% ee); 1H NMR (300 MHz, CDCl3): ¤ 4.42-4.20
(4H, m, -CO2CH2CH3), 4.04 (1H, t, J = 6.0 Hz, Bu-CH), 2.51
(1H, dq, J = 15.1, 7.5 Hz, -C(=N)CH2CH3), 2.28 (1H, dqd,
J = 15.1, 7.5, 1.1 Hz, -C(=N)CH2CH3), 1.75-1.50 (2H, m,
-CH2-), 1.45-1.25 (4H, m, -CH2-), 1.33 (3H, t, J = 7.1 Hz,
-CH3), 1.31 (3H, t, J = 7.1 Hz, -CH3), 1.15 (3H, t, J = 7.6 Hz,
-C(=N)CH2CH3), 0.90 (3H, t, J = 7.0 Hz, -CH3); 13C NMR
(75 MHz, CDCl3): ¤ 166.5, 164.9, 118.5, 84.2, 63.1, 62.7, 49.1,
28.5, 27.9, 22.7, 19.2, 14.0, 13.8, 13.7, 9.3; IR (neat): 2960,
2936, 2874, 1747, 1653, 1458, 1369, 1277, 1230, 1088,
1037 cm¹1; HRMS (ESI): Calcd for C15H26NO6: 316.1754
([M + H]+), Found: 316.1755 ([M + H]+); HPLC analysis:
Daicel Chiralcel OD-H, 235 nm, hexane/2-propanol = 9:1, flow
rate 0.5 mL min¹1, retention time: 12.7 (R) and 14.0 min (S).
Triethyl 3-[(E)-1-(Hydroxyimino)propyl]oxirane-2,2,3-
20
0.933 mmol, 93% yield). ½¡ꢀD 3.01 (c 1.0, CHCl3; 86% ee);
1H NMR (500 MHz, CDCl3): ¤ 7.35-7.31 (3H, m, Ar-H), 7.18-
7.16 (2H, m, Ar-H), 5.19 (1H, s, Ar-CH), 4.35 (1H, dq,
J = 10.7, 7.1 Hz, -CO2CH2CH3), 4.26 (1H, dq, J = 10.7,
7.1 Hz, -CO2CH2CH3), 3.78 (1H, dq, J = 10.7, 7.1 Hz,
-CO2CH2CH3), 3.68 (1H, dq, J = 10.7, 7.1 Hz, -CO2CH2CH3),
2.34 (1H, dq, J = 15.1, 7.8 Hz, -C(=N)CH2CH3), 2.13
(1H, dq, J = 15.4, 7.8 Hz, -C(=N)CH2CH3), 1.30 (3H,
t, J = 7.1 Hz, -CO2CH2CH3), 1.12 (3H, t, J = 7.5 Hz,
-C(=N)CH2CH3), 0.81 (3H, t, J = 7.2 Hz, -CO2CH2CH3);
13C NMR (125 MHz, CDCl3): ¤ 167.2, 165.0, 162.2, 132.8,
129.3, 128.8, 128.6, 91.6, 62.9, 61.9, 61.3, 19.9, 13.9, 13.4,
10.6; IR (neat): 2980, 1768, 1742, 1462, 1452, 1368, 1268,
1228, 1201, 1128, 1081, 1050 cm¹1; HRMS (FAB): Calcd for
C17H22NO5: 320.1498 ([M + H]+), Found: 320.1491
([M + H]+); HPLC analysis: Daicel Chiralpak AD-H, 230
nm, hexane/2-propanol = 9:1, flow rate 0.5 mL min¹1, reten-
tion time: 14.1 (S) and 18.9 min (R).
tricarboxylate (5) (Table 4, Entry 12):
MHz, CDCl3): 8.17 (1H, br, N-OH), 4.36-4.15
1H NMR (300
¤
(6H, m, -CO2CH2CH3), 2.57 (1H, dq, J = 15.2, 7.4 Hz,
-C(=N)CH2CH3), 2.44 (1H, dq, J = 15.1, 7.4 Hz,
-C(=N)CH2CH3), 1.32 (3H, t, J = 7.1 Hz, -CH2CH3), 1.30
(3H, t, J = 7.6 Hz, -CH2CH3), 1.28 (3H, t, J = 7.6 Hz,
-CH2CH3), 1.14 (3H, t, J = 7.6 Hz, -CH2CH3); 13C NMR
(75 MHz, CDCl3): ¤ 164.6, 162.9, 162.8, 153.6, 64.8, 64.7,
63.1, 63.0, 62.7, 19.9, 13.9, 13.8 (two peaks overlap), 9.4; IR
(neat): 3462, 2986, 2942, 1758, 1559, 1466, 1446, 1370, 1253,
1066, 1023 cm¹1; HRMS (ESI): Calcd for C14H22NO8: 332.1338
([M + H]+), Found: 332.1340 ([M + H]+); HPLC analysis:
Daicel Chiralpak AD-H, 230 nm, hexane/2-propanol = 9:1,
flow rate 1.0 mL min¹1, retention time: 8.3 and 9.0 min.
Ethyl (4S,5S)-3-Ethyl-5-(hydroxymethyl)-4-phenyl-4,5-
dihydroisoxazole-5-carboxylate (9).
To a solution of 8
(11.6 mg, 0.036 mmol) in THF (0.5 mL) was added LiAlH(Ot-
Bu)3 (1.0 M in THF solution, 180 ¯L, 0.180 mmol) dropwise at
0 °C, and the cooling bath was then removed.11 The reaction
mixture was stirred for 11 h at room temperature and poured
into ice-cooled 1 M HCl. After neutralization with NaHCO3 the
resulting mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried over Na2SO4, and
concentrated. The resulting residue was purified by flash
column chromatography on silica gel (ethyl acetate/hexane =
1:2 as eluent) to give the title compound 9 (8.7 mg,
Diethyl
2-Hydroxy-2-[(S)-2-(hydroxyimino)-1-phenyl-
butyl]malonate (7). To a solution of 6 (200 mg, 0.60 mmol)
in MeOH (8 mL) was stirred for 3 h in the presence of 5%
palladium on activated carbon (80 mg) at room temperature
under H2 atmosphere. The resulting mixture was filtered to
remove the catalyst, and the filtrate was concentrated. Purifi-
cation of the residue by column chromatography on silica gel
(ethyl acetate/hexane = 1:1 as eluent) gave the title compound
20
20
7 (188 mg, 0.56 mmol, 93% yield). ½¡ꢀD 1.68 (c 1.0, CHCl3;
0.031 mmol, 87% yield). ½¡ꢀD 0.68 (c 0.5, CHCl3; 85% ee);
86% ee); 1H NMR (500 MHz, CDCl3): ¤ 7.36-7.34 (2H, m,
Ar-H), 7.32-7.27 (3H, m, Ar-H), 7.12 (1H, br, OH), 4.90 (1H,
br, OH), 4.63 (1H, s, Ar-CH), 4.31 (1H, dq, J = 10.7, 7.1 Hz,
-CO2CH2CH3), 4.27 (1H, dq, J = 10.7, 7.1 Hz, -CO2CH2CH3),
4.08 (1H, dq, J = 10.7, 7.2 Hz, -CO2CH2CH3), 4.04 (1H, dq,
J = 10.7, 7.2 Hz, -CO2CH2CH3), 2.54 (1H, dq, J = 13.5,
7.6 Hz, -C(=N)CH2CH3), 1.86 (1H, dq, J = 13.5, 7.6 Hz,
-C(=N)CH2CH3), 1.31 (3H, t, J = 7.1 Hz, -CO2CH2CH3),
1.09 (3H, t, J = 7.2 Hz, -CO2CH2CH3), 1.00 (3H, t, J =
7.6 Hz, -C(=N)CH2CH3); 13C NMR (125 MHz, CDCl3): ¤
1H NMR (500 MHz, CDCl3): ¤ 7.34-7.28 (3H, m, Ar-H), 7.14-
7.12 (2H, m, Ar-H), 4.43 (1H, s, Ar-CH), 3.92 (1H, dd,
J = 11.8, 5.8 Hz, -CCH2OH), 3.86 (1H, dd, J = 11.8, 8.5 Hz,
-CCH2OH), 3.74 (2H, q, J = 7.2 Hz, -CO2CH2CH3), 2.54 (1H,
dd, J = 8.2, 6.4 Hz, -CCH2OH), 2.34 (1H, dq, J = 15.1,
7.8 Hz, -C(=N)CH2CH3), 2.12 (1H, dq, J = 14.6, 7.6 Hz,
-C(=N)CH2CH3), 1.11 (3H, t, J = 7.5 Hz, -C(=N)CH2CH3),
0.84 (3H, t, J = 7.2 Hz, -CO2CH2CH3); 13C NMR (125 MHz,
CDCl3): ¤ 168.8, 161.9, 133.7, 129.0, 128.7, 128.4, 92.1, 65.5,
61.5, 61.3, 20.1, 13.5, 10.7; IR (neat): 3349, 2979, 2927, 1745,

1064 Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011)
Asymmetric Synthesis of Isoxazoline-N-oxides
1461, 1453, 1371, 1277, 1244, 1129, 1096, 1076, 1055,
1040 cm¹1; HRMS (FAB): Calcd for C15H20NO4: 278.1392
([M + H]+), Found: 278.1388 ([M + H]+); HPLC analysis:
Daicel Chiralpak AD-H, 230 nm, hexane/2-propanol = 9:1,
flow rate 1.0 mL min¹1, retention time: 14.0 (4S,5S) and
18.9 min (4R,5R).
17.6 min (4R,5R).
(3S,4S,5R)-3-(Benzyloxymethyl)-5-ethyl-3-hydroxy-4-
phenylpyrrolidin-2-one (11). To a solution of 10 (7.4 mg,
0.02 mmol) in a 3:1 mixture of MeOH/THF (0.3 mL) was
added NiCl2•6H2O (14.2 mg, 0.06 mmol) at ¹40 °C. After
10 min of stirring, NaBH4 (7.4 mg, 0.20 mmol) was added
portionwise. The stirring was maintained at ¹40 °C for 2 h, and
the reaction was quenched with 5 M HCl. After the reaction
mixture was poured into K2CO3 and 28% ammonia solution at
0 °C, the mixture was stirred for 1 h at 0 °C. The reaction
mixture was extracted with ethyl acetate, dried over sodium
sulfate, and concentrated. The resulting residue was purified by
flash column chromatography on silica gel (chloroform/
methanol = 50:1 as eluent) to give the title compound 11
Crystal Structure Analysis of Ethyl (4S,5S)-3-Ethyl-5-
(hydroxymethyl)-4-phenyl-4,5-dihydroisoxazole-5-carbox-
ylate (9):
Single crystals of 9 for X-ray diffraction
experiments were recrystallized from EtOH. The data
were collected at ¹177 °C on a Rigaku R-AXIS RAPID
IP area detector with graphite-monochromated Mo K¡
radiation (- = 0.71075 ¡). The crystal structure was solved
by direct methods using SIR9221 and expanded using
DIRDIF99 Fourier techniques.22 The non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were refined
isotropically. The final cycle of full-matrix least-squares
refinement23 on F2 was based on 3087 observed reflections
and 257 variable parameters. Crystallographic data for (c):
C15H19NO4, colorless prism, 0.5 © 0.4 © 0.3 mm3, monoclinic,
P21, a = 9.0974(10), b = 7.7565(9), c = 10.9278(14) ¡, V =
724.14(15) ¡3, Dcalcd = 1.272 g cm¹3, Z = 2, 2ªmax = 54.9°,
® = 0.921 cm¹1. A total of 7136 reflections were measured.
R = 0.047, and Rw = 0.111 for all reflections. All calculations
were performed using the CrystalStructure3.824 crystallograph-
ic software package. Crystallographic data have been deposited
with Cambridge Crystallographic Data Centre: Deposition
number CCDC-794861 for compound 9. Copies of the data
can be obtained free of charge via http://www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge, CB2
1EZ, U.K.; Fax: +44 1223 336033; e-mail: deposit@ccdc.
cam.ac.uk).
20
(6.1 mg, 0.019 mmol, 93% yield). ½¡ꢀD 0.43 (c 0.5, CHCl3;
85% ee); 1H NMR (300 MHz, CDCl3): ¤ 7.35-7.23 (6H, m, Ar-
H), 7.19-7.15 (2H, m, Ar-H), 7.11-7.08 (2H, m, Ar-H), 6.47
(1H, br, NH), 4.38 (1H, d, J = 11.9 Hz, ArCH2O-), 4.21 (1H,
d, J = 11.9 Hz, ArCH2O-), 4.18-4.10 (1H, m, CH3CH2CH-),
3.56 (1H, d, J = 10.2 Hz, ArCH2OCH2), 3.60-3.45 (1H, br,
OH), 3.46 (1H, d, J = 5.5 Hz, Ar-CH), 3.24 (1H, d,
J = 10.2 Hz, ArCH2OCH2), 1.44-1.32 (1H, m, CH3CH2-),
1.30-1.18 (1H, m, CH3CH2-), 0.79 (3H, t, J = 7.4 Hz,
CH3CH2-); 13C NMR (75 MHz, CDCl3): ¤ 176.0, 137.5,
135.7, 129.7, 128.3, 128.2, 127.6 (two peaks overlap), 127.3,
79.5, 73.6, 69.9, 57.4, 55.7, 23.6, 10.5; IR (neat): 3292, 3064,
3030, 2963, 2872, 1704, 1699, 1494, 1454, 1381, 1102 cm
¹1
;
HRMS (FAB): Calcd for C20H24NO3: 326.1756 ([M + H]+),
Found: 326.1763 ([M + H]+); HPLC analysis: Daicel
Chiralpak AD-H, 215 nm, hexane/EtOH = 4:1, flow rate 0.5
mL min¹1, retention time: 26.6 (3S,4S,5R) and 29.7 min
(3R,4R,5S).
Crystal Structure Analysis of (3S,4S,5R)-3-(Benzyloxy-
methyl)-5-ethyl-3-hydroxy-4-phenylpyrrolidin-2-one (11):
Single crystals of 11 for X-ray diffraction experiments were
recrystallized from MeCN. The data were collected at ¹177 °C
on a Rigaku R-AXIS RAPID IP area detector with graphite-
monochromated Mo K¡ radiation (- = 0.71075 ¡). The crystal
structure was solved by direct methods using SIR9221 and
expanded using DIRDIF99 Fourier techniques.22 The non-
hydrogen atoms were refined anisotropically. Hydrogen atoms
attached to N and O were refined isotropically. Other hydrogen
atoms were refined using the riding model. The final cycle
of full-matrix least-squares refinement23 on F2 was based on
3447 observed reflections and 246 variable parameters.
Crystallographic data for (c): C20H23NO3, colorless platelet,
1.0 © 0.4 © 0.06 mm3, monoclinic, P21, a = 10.7063(3),
Ethyl (4S,5S)-5-(Benzyloxymethyl)-3-ethyl-4-phenyl-4,5-
dihydroisoxazole-5-carboxylate (10).
To a solution of
9 (35.0 mg, 0.126 mmol) in DMF (0.25 mL) was added Ag2O
(146 mg, 0.630 mmol) and BnBr (2.16 g, 12.6 mmol) at room
temperature. The reaction flask was covered with aluminum
foil and stirred for 11 h at room temperature. The mixture was
filtered through a pad of celite, and concentrated. The resulting
residue was purified by flash column chromatography on silica
gel (hexane/ethyl acetate = 20:1 to 4:1 as eluent) to give the
20
title compound 10 (43.6 mg, 0.118 mmol, 94% yield). ½¡ꢀD
1
0.78 (c 0.5, CHCl3; 85% ee); H NMR (300 MHz, CDCl3): ¤
7.40-7.25 (8H, m, Ar-H), 7.12-7.05 (2H, m, Ar-H), 4.69 (2H,
s, ArCH2O-), 4.27 (1H, s, Ar-CH), 3.90 (1H, d, J = 10.7 Hz,
ArCH2OCH2), 3.86 (1H, d, J = 10.7 Hz, ArCH2OCH2), 3.73
(1H, dq, J = 10.6, 7.2 Hz, -CO2CH2CH3), 3.68 (1H, dq,
J = 10.5, 7.1 Hz, -CO2CH2CH3), 2.32 (1H, dq, J = 15.2,
7.7 Hz, -C(=N)CH2CH3), 2.07 (1H, dq, J = 15.3, 7.7 Hz,
-C(=N)CH2CH3), 1.07 (3H, t, J = 7.5 Hz, -C(=N)CH2CH3),
0.82 (3H, t, J = 7.1 Hz, -CO2CH2CH3); 13C NMR (75 MHz,
CDCl3): ¤ 168.1, 161.3, 137.8, 133.9, 128.9, 128.7, 128.4,
128.3, 127.8, 127.7, 92.7, 73.9, 72.9, 61.33, 61.31, 20.0, 13.5,
10.7; IR (neat): 3251, 2967, 2931, 2875, 1703, 1495, 1453,
1100, 1080 cm¹1; HRMS (FAB): Calcd for C22H26NO4:
368.1862 ([M + H]+), Found: 368.1876 ([M + H]+); HPLC
analysis: Daicel Chiralpak AD-H, 215 nm, hexane/EtOH =
4:1, flow rate 0.5 mL min¹1, retention time: 14.7 (4S,5S) and
b = 7.2476(2), c = 11.5374(5) ¡, ¢ = 109.4732(11)°, V =
844.18(5) ¡3,
Dcalcd = 1.280 g cm , Z = 2, 2ªmax = 54.9°,
¹3
® = 0.855 cm¹1. R = 0.029, and Rw = 0.082 for all reflec-
tions. All calculations were performed using the CrystalStruc-
ture3.824 crystallographic software package. Crystallographic
data have been deposited with Cambridge Crystallographic
Data Centre: Deposition number CCDC-827004 for compound
9. Copies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, U.K.; Fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).

T. Kano et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 10 (2011) 1065
a) M. C. Maestro, M. C. Barquilla, M. R. Martín,
5
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. We thank Mr. Masahiko Bando
for X-ray crystallographic expertise, and Dr. Masakazu
Nagasawa and Ms. Kayoko Yamamoto for mass-spectrometric
analysis.
Tetrahedron: Asymmetry 1999, 10, 3593. b) C.-Y. Zhu, X.-M.
Deng, X.-L. Sun, J.-C. Zheng, Y. Tang, Chem. Commun. 2008,
738. c) C.-Y. Zhu, X.-L. Sun, X.-M. Deng, J.-C. Zheng, Y. Tang,
Tetrahedron 2008, 64, 5583. d) C. Zhong, L. N. S. Gautam, J. L.
Petersen, N. G. Akhmedov, X. Shi, Chem.®Eur. J. 2010, 16, 8605.
Supporting Information
6
a) H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V.
Marcos, K. A. Jørgensen, Angew. Chem., Int. Ed. 2009, 48, 6844.
b) Z. Shi, B. Tan, W. W. Y. Leong, X. Zeng, M. Lu, G. Zhong, Org.
Lett. 2010, 12, 5402; See also Ref. 2a.
1H and 13C spectra for isoxazoline-N-oxides and compounds
5-11. This material is available free of charge on the web at
http://www.csj.jp/journals/bcsj/.
7
J. C. Le Menn, J. Sarrazin, A. Tallec, Bull. Soc. Chim. Fr.
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2
2 2
23 Least-squares function minimized: -w(Fo ¹ Fc ) where
w: Least-squares weights.
24 CrystalStructure 3.8: Crystal Structure Analysis Package,
Rigaku and Rigaku Americas, 2000-2007. 9009 New Trails Dr.
The Woodlands TX 77381 USA.