Catalytic enantioselective synthesis of carboxy-substituted 2-isoxazolines by cascade oxa-Michael-cyclization

Article abstract of DOI:10.1039/c7ob02722b

An efficient quinidine-based phase-transfer-catalyzed enantioselective cascade oxa-Michael-cyclization reaction of hydroxylamine with various β-carboxy-substituted α,β-unsaturated ketones has been achieved for the preparation of chiral carboxy-substituted 2-isoxazolines. This cascade reaction provided the desired products in good yields (up to 98%) with excellent enantioselectivities (91-96% ee). In addition, the cascade reaction was effectively applied to the first catalytic asymmetric synthesis of the herbicide (S)-methiozolin.

Full text of DOI:10.1039/c7ob02722b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Catalytic enantioselective synthesis of carboxy-substituted 2-isoxazolines by
cascade oxa-Michael-cyclization
Hyo-Jun Lee,a Bora Eun,a Eonseon Sung,a Gil Tae Hwang,a Young Kwan Kob and
Chang-Woo Cho*a
aDepartment of Chemistry and Green-Nano Materials Research Center,
Kyungpook National University, Daegu 41566, Republic of Korea
bCenter for Eco-Friendly New Materials, Korea Research Institute of Chemical
Technology, Daejeon 34114, Republic of Korea
*Corresponding author. E-mail: cwcho@knu.ac.kr; Fax: +82-53-950-6330; Tel: +82-53-
950-5334
1

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Abstract
An efficient quinidine-based phase-transfer-catalyzed enantioselective cascade oxa-
Michael‒cyclization reaction of hydroxylaminewith various -carboxy-substituted -
unsaturated ketones has been achieved for the preparation of chiral carboxy-substituted
2-isoxazolines. This cascade reaction provided the desired products in good yields (up
to 98%) with excellent enantioselectivities (91−96% ee). In addition, the cascade
reaction was effectively applied to the first catalytic asymmetric synthesis of the
herbicide (S)-methiozolin.
2

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Introduction
2-Isoxazolines are an important class of heterocycles found in natural products,1
pharmaceuticals2 and agrochemicals3 displaying a variety of potent biological activities.
In addition, 2-isoxazolines have been widely used as versatile synthons4 and chiral
ligands5 in synthetic organic chemistry. For this reason, 2-isoxazoline synthesis has
attracted significant attention.6 In particular, the asymmetric synthesis of optically pure
2-isoxazolines has been a subject of active research.7 As an example of the importance
of enantiopure 2-isoxazolines (Fig. 1), biological evaluation of the antiparasitic
isoxazoline Bravecto (fluralaner) revealed that only the S enantiomer of Bravecto is
active and the R enantiomer is inactive.8
N
O
Me
R
CF3
Me
F
N
O
Me
Cl
O
S
F
Cl
R = C(O)NHCH2C( O)NHCH2CF3
(S)-Bravecto, bioactive
(R enantiomer: inactive)
(S)-Methiozolin, bioactive
(R enantiomer: inactive)
Fig. 1 Examples of bioactive chiral 2-isoxazolines.
In addition, in our previous paper,9 it was reported that only the (S)-methiozolin, which
was synthesized from enantiopure (S)-[5-methyl-3-(3-methylthiophen-2-yl)-4,5-
3

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dihydroisoxazol-5-yl]methanol prepared by chiral prep-HPLC separation, displayed
herbicidal activities against grass weeds. Interestingly, (R)-methiozolin showed no
herbicidal activities. Methiozolin has been commercialized as a racemic herbicide
displaying an efficacious and toxicologically favorable activity against grass weed in
turf grass.10 Therefore, owing to the environment-friendly and atom-economic
importance, development of an enantioselective route for the efficient synthesis of (S)-
methiozolin is highly desirable. Here, we report an asymmetric phase-transfer-catalyzed
cascade oxa-Michael‒cyclization reaction of various -carboxy-substituted ,-
unsaturated ketones with hydroxylamine that affords the desired chiral carboxy-
substituted 2-isoxazolines in good yields with excellent enantioselectivities (Scheme 1).
The cascade reaction is effectively applied to the first catalytic asymmetric synthesis of
(S)-methiozolin. Although the enantioselective phase-transfer-catalyzed cascade
synthesis11−13 of chiral trifluoromethyl-substituted 2-isoxazolines with -
trifluoromethyl-substituted ,-unsaturated ketones and hydroxylamine has been well
developed by Shibata’s group,7d to the best our knowledge, the use of -carboxy-
substituted ,-unsaturated ketones as substrates in the cascade reaction has not been
reported. In particular, the carboxy group in the cascade product can be transformed to
versatile functional groups.
4

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R2
N
O
O
R2
O
asymmetric
phase-transfer-
catalyzed
OtBu
Ot Bu
R1
R1
+
O
cascade reaction
HONH2
18 examples
up to 98% yield
91-96% ee
Me
F
N
O
Me
i) reduction
O
ii) benzylation
S
(S)-Methiozolin
F
Scheme 1 Enantioselective phase-transfer-catalyzed cascade reaction of -carboxy-
substituted ,-unsaturated ketones with hydroxylamine and its application to synthesis
of (S)-methiozolin.
Results and discussion
To explore the feasibility of the enantioselective phase-transfer-catalyzed cascade oxa-
Michael-cyclization reactions of -carboxy-substituted ,-unsaturated ketones with
hydroxylamine,14 the cascade reactions of (E)-tert-butyl 2-methyl-4-oxo-4-phenylbut-2-
enoate (1a) and hydroxylamine with potassium hydroxide as the base additive in
toluene at −30 °C were performed in the presence of quinidine-based phase-transfer
catalysts I−VIII, respectively (Table 1, entries 1−8). Among all the catalysts assayed,
catalyst VIII proved to be the best and provided the corresponding cascade product 2a
in 68% yield and 73% ee. Varying the solvent revealed that methyl tert-butyl ether
(MTBE) was ideal for the cascade reaction under otherwise identical conditions,
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affording 2a in 94% yield and 83% ee (Table 1, entries 9−13). Finally, among the base
additives tested, cesium carbonate was ideal for the cascade reaction to provide the
desired cascade product 2a in 92% yield and 93% ee. (Table 1, entries 14−17). When
the loadings of hydroxylamine and cesium carbonate were decreased to 2 equiv and 2.2
equiv, respectively, 2a was obtained in 94% ee, but with a considerably decreased yield
of 54% (Table 1, entry 18). In addition, lowering the reaction temperature to −40 °C
provided 2a in 95% ee, with a drastically decreased yield of 15% (Table 1, entry 19).
Table 1 Optimization of the enantioselective phase-transfer-catalyzed cascade oxa-
Michael-cyclization reactions of (E)-tert-butyl 2-methyl-4-oxo-4-phenylbut-2-enoate
(1a) with hydroxylaminea

catalyst I VIII (10 mol %)
HONH2 (aq. 50 wt%, 3 equiv)
base (3.3 equiv)
O
Me
N
O
Me
O
OtBu
OtBu
Ph
Ph
solvent (0.1 M)
30 oC, 24 h
O
1a
2a
Br
OMe
+
H
N
I, Ar = 4-(CF3)C6H4
II, Ar = 9-Anthracyl
V
,
Ar = 3,5-(1-Naph)2C6H3
Ar
VI, Ar = 3,5-(2-Naph)2C6H3
OH
III, Ar = 3,5-tBu2C6H3 VII, Ar = 3,5-(CF3)2C6H3
N
VIII, Ar = 2,5-(CF3)2C6H3
IV, Ar = 3,5-Ph2C6H3
Yieldc
(%)
eed
(%)
Entry
Catalyst
Baseb
KOH
KOH
KOH
KOH
Solvent
toluene
toluene
toluene
toluene
1
2
3
4
I
75
77
76
61
28
25
61
46
II
III
IV
6

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5
6
V
KOH
KOH
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
THF
71
71
67
68
78
65
78
82
94
n.r.e
19
63
92
54
15
44
68
54
73
71
71
76
66
83
VI
7
VII
KOH
8
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
VIII
KOH
9
KOH
10
11
12
13
14
15
16
17
18f
19g
KOH
KOH
KOH
Et2O
KOH
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
Cs2CO3
Cs2CO3
90
93
93
94
95
aProcedure: HONH2 (0.6 mmol) was added to a mixture of 1a (0.2 mmol), catalyst (0.02 mmol), and base
(0.66 mmol) in 2 mL of the solvent in one portion. The mixture was stirred at −30 °C for 24 h. bKOH was
used as 50 wt% aqueous solution. Na2CO3, K2CO3, Rb2CO3, and Cs2CO3 were solids and used as such.
d
e
f
cIsolated yield. Determined by chiral HPLC analysis (Chiralpak AD-H). No reaction. 2 equiv of
HONH2 and 2.2 equiv of Cs2CO3 were used. gAt −40 °C.
Subsequently, the scope of the -carboxy-substituted ,-unsaturated ketones in the
enantioselective phase-transfer-catalyzed cascade oxa-Michael‒cyclization reactions
with hydroxylamine was explored under the optimized conditions (Tables 2 and 3). First,
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the reactions of hydroxylamine with a series of 4-substituted (E)-tert-butyl 2-methyl-4-
oxobut-2-enoate 1 bearing aryl, electron-deficient aryl, electron-rich aryl, heteroaryl,
and substituted heteroaryl substituents gave the corresponding cascade products 2a−2i
in good yields and excellent enantioselectivities (Table 2).15 Further investigation of the
enantioselective phase-transfer-catalyzed cascade reactions with hydroxylamine was
then carried out with an assortment of 2-substituted (E)-tert-butyl 4-oxo-4-phenylbut-2-
enoate 1 bearing alkyl, substituted alkyl, protected hydroxyalkyl, benzyl-protected
mercaptoalkyl, and doubly N-protected aminoalkyl substituents (Table 3). In all cases,
the desired cascade products 2j−2r were obtained in good yields and excellent
enantioselectivities.
8

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Table 2 Enantioselective phase-transfer-catalyzed cascade oxa-Michael‒cyclization
reactions of hydroxylamine with various 4-substituted (E)-tert-butyl 2-methyl-4-oxobut-
2-enoates 1a
catalyst VIII (10 mol %)
HONH2 (aq. 50 wt%, 3 equiv)
Cs2CO3 (3.3 equiv)
O
Me
N
O
Me
O
OtBu
OtBu
R1
R1
MTBE (0.1 M)
30 oC, 24 h
1
2a2i
O

N
O
N O
Me
Me
O
OtBu
OtBu
O
2a
92% yield, 93% ee
2b
84% yield, 94% ee
N
O
N
O
Br
Me
Me
O
OtBu
OtBu
X
O
2c
97% yield, 92% ee
2d, X = I: 75% yield, 92% ee
2eb, X = Me: 95% yield, 92% ee
N
O
N
O
O
Me
O
Me
OtBu
OtBu
O
O
2fb
2g
O
82% yield, 91% ee
98% yield, 91% ee
Me
N
O
N
O
Me
O
Me
O
OtBu
OtBu
S
S
2h
2ib
90% yield, 93% ee
91% yield, 93% ee
aProcedure: HONH2 (0.6 mmol) was added to a mixture of 1 (0.2 mmol), catalyst VIII (0.02 mmol), and
Cs2CO3 (0.66 mmol) in MTBE (2 mL) in one portion. The mixture was stirred either at −20 or −30 °C for 24 h.
Enantiomeric excess was determined by chiral HPLC analysis (Chiralpak AD-H). bAt −20 °C.
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Table 3 Enantioselective phase-transfer-catalyzed cascade oxa-Michael‒cyclization
reactions of hydroxylamine with various 2-substituted (E)-tert-butyl 4-oxo-4-phenylbut-
2-enoates 1a
catalyst VIII (10 mol %)
HONH2 (aq. 50 wt%, 3 equiv)
O
R2
N
O
Cs2CO3 (3.3 equiv)
R2
O
OtBu
Ot Bu
Ph
Ph
MTBE (0.1 M)

30 oC, 24 h
1
2j2r
O
Me
Me
Me
Ot Bu
Ph
OtBu
N
O
N
O
N
O
OtBu
Ph
Ph
Ph
O
O
81% yield, 92% ee
O
2j
2k
2l
80% yield, 94% ee
81% yield, 96% ee
CN
CH2
OBn
OtBu
N
O
N
O
N
O
OtBu
Ot Bu
Ph
Ph
Ph
O
O
O
2m
2n
2o
85% yield, 91% ee
79% yield, 93% ee
81% yield, 94% ee
Boc
N
Cbz
n = 2
OTBS
OtBu
SBn
Ot Bu
N
O
N
O
N
O
OtBu
Ph
Ph
Ph
O
O
O
2p
2q
2r
80% yield, 93% ee
93% yield, 95% ee
86% yield, 92% ee
aProcedure: HONH2 (0.6 mmol) was added to a mixture of 1 (0.2 mmol), catalyst VIII (0.02 mmol), and
Cs2CO3 (0.66 mmol) in MTBE (2 mL) in one portion. The mixture was stirred at −30 °C for 24 h. Enantiomeric
excess was determined by chiral HPLC analysis (Chiralpak AD-H).
To further investigate the feasibility of scaling-up the cascade reaction, the
enantioselective phase-transfer-catalyzed cascade reaction was carried out on a large
scale, as shown in Scheme 2. The reaction successfully provided the desired cascade
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product 2i in 90% yield and 91% ee. The cascade product 2i was transformed to (S)-
methiozolin (4) in two steps. Reduction of 2i with sodium borohydride in ethanol at
room temperature resulted in the formation of alcohol 3 in 95% yield. Benzylation of 3
with 2-(chloromethyl)-1,3-difluorobenzene and sodium hydroxide in tetrahydrofuran
provided (S)-methiozolin (4) in 77% yield.9
catalyst VIII
(10 mol %)
HONH2
(aq. 50 wt%, 3 equiv)
Cs2CO3 (3.3 equiv)
Me
O
Me
Me
N
O
Me
O
OtBu
Ot Bu
S
MTBE (0.1 M)

S
O
1i
(1.1 g, 4.1 mmol)
2i
20 oC, 24 h
90% yield, 91% ee
(1.04 g, 3.7 mmol)
F
(1.2 equiv)
Cl
Me
N
O
F
Me
NaBH4 (3 equiv)
NaOH (2.2 equiv)
OH
EtOH (0.3 M)
rt, 24 h
THF (0.2 M)
40 oC, 15 min to
70 oC, 4 h
S
3
95% yield
Me
F
N
O
Me
O
S
F
4, (S)-Methiozolin
77% yield
Scheme 2 Synthesis of (S)-methiozolin via a large-scale enantioselective phase-transfer-
catalyzed cascade reaction.
The absolute stereochemical assignment of all cascade products was based on the
absolute stereochemistry of 3, which was determined to be the S configuration by
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comparing the specific rotation of 3 with that reported in the literature.9 Based on the
absolute stereochemistry of the cascade products, the proposed transition state of the
cascade reaction is depicted in Fig. 2. The substrate is presumably captured by the
catalyst via hydrogen bonding between the carbonyl oxygen in the substrate and the
chiral secondary hydroxyl group in the catalyst. The anionic hydroxylamine nucleophile,
which is generated by the deprotonation of hydroxylamine by the base additive, would
form an ion pair with the ammonium cation in the catalyst and be thus optimally
positioned between the catalyst and the substrate. Therefore, the oxa-Michael reaction
of the anionic hydroxylamine nucleophile takes place from the Si face of the substrate to
afford the oxa-Michael intermediate. The subsequent intramolecular imine formation
provides the desired cascade product.
N+
CF3
N
O
F3C
NH2O
H
OMe
Si face attack
O
Me
O
O
Fig. 2 Proposed transition state of the cascade reaction.
12

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Conclusion
In conclusion, the enantioselective phase-transfer-catalyzed cascade oxa-
Michael‒cyclization reaction of -carboxy-substituted ,-unsaturated ketones with
hydroxylamine has been achieved by using the quinidine-based phase-transfer catalyst
VIII and cesium carbonate as the base additive. The cascade reaction provided the
highly enantioenriched carboxy-substituted 2-isoxazolines as the cascade products in
good yields (up to 98%) with excellent enantioselectivities (91−96% ee). This is the
only example of the use of -carboxy-substituted ,-unsaturated ketones as a substrate
in the enantioselective phase-transfer-catalyzed cascade oxa-Michael‒cyclization
reaction with hydroxylamine. In addition, the cascade reaction was effectively applied
to the first catalytic asymmetric synthesis of the herbicide (S)-methiozolin. Thus, the
developed strategy provides a convenient synthetic route for generating various chiral
carboxy-substituted 2-isoxazolines. Further applications of these species in the synthesis
of bioactive compounds are being studied.
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Experimental
General
1H and 13C NMR spectra were recorded on a 500 MHz spectrometer with
tetramethylsilane as the internal reference. Mass spectroscopic data were obtained from
the Korea Basic Science Institute (Daegu) with a JEOL JMS 700 high resolution mass
spectrometer. Enantiomeric excess values were determined by HPLC analysis with
chiral stationary phase column (Chiralpak AD-H).-Carboxy-substituted -
unsaturated ketones 1 were prepared according to the reported procedures.16
Preparation of catalysts I−VIII.
Catalysts I−VII were prepared according to the reported procedures.17
1-[2,5-Bis(trifluoromethyl)benzyl]-2-[(S)-hydroxy(6-methoxyquinolin-4-
yl)methyl]-8-vinyl-1-azoniabicyclo[2.2.2]octane bromide (catalyst VIII).
2,5-Bis(trifluoromethy)benzyl bromide (0.47 mL, 2.6 mmol) was added to a solution of
quinidine (648 mg, 2 mmol) in THF (10 mL, 0.2 M) at rt, and then the mixture was
allowed to stir at reflux. After 12 h, the mixture was cooled to rt. The solvent was
removed and the residue was purified by silica gel column chromatography (SiO2, 7%
MeOH in CHCl3) to provide the catalyst VIII in 63% yield (798 mg, 1.26 mmol) as a
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white solid. mp 177−178 °C; []D 24 122.2 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) 
8.68 (s, 1H), 8.64 (d, J = 4.5 Hz, 1H), 7.96−7.94 (m, 2H), 7.91−7.89 (m, 1H), 7.83 (d, J
= 4.5 Hz, 1H), 7.30 (dd, J = 9.0, 2.5 Hz, 1H), 6.81 (d, J = 4.5 Hz, 1H), 6.57 (s, 1H),
6.43 (d, J = 13.0 Hz, 1H), 6.07−6.00 (m, 1H), 5.47 (d, J = 12.0 Hz, 1H), 5.29−5.22 (m,
2H), 4.79−4.75 (m, 1H), 4.17 (s, 1H), 4.05−4.02 (m, 1H), 3.96 (s, 3H), 3.41−3.37 (m,
1H), 2.90−2.83 (m, 1H), 2.58−2.48 (m, 2H), 2.06 (s, 1H), 1.96 (s, 1H), 1.92−1.83 (m,
2H), 1.08−1.03 (m, 1H); 13C NMR (125 MHz, CDCl3)  158.2, 146.8, 143.7, 142.4,
135.3, 134.4 (q, 2JC-F = 6.2 Hz), 134.2 (q, 2JC-F = 10.0 Hz), 133.9, 131.2, 128.8 (q, 3JC-F
1
= 5.0 Hz), 127.8, 126.5, 125.8, 123.9 (q, JC-F = 91.2 Hz), 121.8, 121.7 (q, 1JC-F = 88.7
Hz), 120.6, 118.0, 100.9, 69.1, 65.7, 58.0, 56.5, 55.9, 55.3, 37.7, 26.5, 23.7, 21.7; FTIR
(neat) 3182, 2949, 1621, 1508, 1422, 1304, 1240, 1173, 1125, 1095, 1045, 826, 747 cm-
1; HRMS (FAB) calcd for [M–Br]+ C29H29F6N2O2 551.2133, found 551.2131.
Typical procedure for the synthesis of racemic carboxy-substituted 2-isoxazolines 2.
Hydroxylamine (50 wt% in H2O) (0.6 mmol) was added to a mixture of substrate 1 (0.2
mmol), hexadecyltrimethylammonium bromide (0.06 mmol), and potassium hydroxide
(2 mmol) in ClCH2CH2Cl (2 mL) in one portion. The mixture was stirred at rt for 0.5 h.
The mixture was quenched by 1 N HCl and extracted with CH2Cl2. The organic layer
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was washed with brine and dried with MgSO4. Filtration, concentration, and
purification by flash column chromatography (SiO2, 5−20% EtOAc in hexanes)
provided the corresponding racemic carboxy-substituted 2-isoxazolines 2.
Typical procedure for the enantioselective phase-transfer-catalyzed cascade oxa-
Michael−cyclization reactions of hydroxylamine to -carboxy-substituted -
unsaturated ketones.
Hydroxylamine (50 wt% in H2O) (0.6 mmol) was added to a mixture of substrate 1 (0.2
mmol), catalyst VIII (0.02 mmol), and cesium carbonate (0.66 mmol) in MTBE (2 mL)
in one portion. The mixture was stirred either at −20 or −30 °C for 24 h. The mixture
was quenched by 1 N HCl and extracted with EtOAc. The organic layer was washed
with brine and dried with MgSO4. Filtration, concentration, and purification by flash
column chromatography (SiO2, 5−20% EtOAc in hexanes) provided the corresponding
cascade products 2.
(S)-tert-Butyl
5-methyl-3-phenyl-4,5-dihydroisoxazole-5-carboxylate
(2a).
White solid (48 mg, 92%); mp 48−49 °C; []D 24 174.4 (c 1, CHCl3, 93% ee); 1H NMR
(500 MHz, CDCl3)  7.67−7.65 (m, 2H), 7.41−7.38 (m, 3H), 3.84 (d, J = 17.0 Hz, 1H),
13
3.15 (d, J = 17.0 Hz, 1H), 1.66 (s, 3H), 1.49 (s, 9H); C NMR (125 MHz, CDCl3) 
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170.8, 155.9, 130.1, 129.2, 128.6, 126.6, 86.5, 82.3, 44.3, 27.7, 23.5; FTIR (neat) 2983,
2931, 1726, 1446, 1364, 1301, 1151, 1098, 906, 757, 686 cm-1; HRMS (EI) calcd for
[M]+ C15H19NO3 261.1365, found 261.1367; HPLC (Chiralpak AD-H, hexane/IPA =
95/5, 0.9 mL/min,  = 254 nm) tR = 7.9 min (minor isomer), 13.3 min (major isomer).
(S)-tert-Butyl 5-methyl-3-(naphthalen-2-yl)-4,5-dihydroisoxazole-5-carboxylate
24
(2b). White solid (52 mg, 84%); mp 137−138 °C; []D 205.4 (c 1, CHCl3, 94% ee);
1H NMR (500 MHz, CDCl3)  7.96 (dd, J = 9.0, 1.5 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H),
7.85−7.83 (m, 3H), 7.54−7.49 (m, 2H), 3.96 (d, J = 17.0 Hz, 1H), 3.28 (d, J = 17.0 Hz,
1H), 1.70 (s, 3H), 1.51 (s, 9H); 13C NMR (125 MHz, CDCl3)  170.8, 156.1, 133.9,
132.8, 128.4, 128.2, 127.7, 127.0, 126.8, 126.8, 126.6, 123.4, 86.7, 82.3, 44.3, 27.8,
23.6; FTIR (neat) 2922, 2853, 1724, 1461, 1369, 1302, 1260, 1156, 1089, 917, 826, 752
cm-1; HRMS (EI) calcd for [M]+ C19H21NO2 311.1521, found 311.1522; HPLC
(Chiralpak AD-H, hexane/IPA = 92/8, 0.9 mL/min,  = 254 nm) tR = 7.9 min (minor
isomer), 16.9 min (major isomer).
(S)-tert-Butyl 3-(3-bromophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate
24
1
(2c). White solid (66 mg, 97%); mp 59−60 °C; []D 137.0 (c 1, CHCl3, 92% ee); H
NMR (500 MHz, CDCl3)  7.79 (t, J = 1.5 Hz, 1H), 7.59 (dt, J = 8.0, 1.0 Hz, 1H), 7.53
(dq, J = 8.0, 1.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 3.80 (d, J = 17.0 Hz, 1H), 3.11 (d, J =
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13
17.0 Hz, 1H), 1.66 (s, 3H), 1.49 (s, 9H); C NMR (125 MHz, CDCl3)  170.5, 154.8,
132.9, 131.2, 130.1, 129.5, 125.1, 122.7, 86.9, 82.4, 44.0, 27.7, 23.5; FTIR (neat) 2980,
2933, 1741, 1719, 1553, 1367, 1307, 1148, 1088, 908, 841, 786 cm-1; HRMS (EI) calcd
for [M]+ C15H18BrNO3 339.0470, found 339.0473; HPLC (Chiralpak AD-H, hexane/IPA
= 90/10, 0.9 mL/min,  = 254 nm) tR = 5.7 min (minor isomer), 8.1 min (major isomer).
(S)-tert-Butyl
3-(4-iodophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate
(2d). Yellow solid (58 mg, 75%); mp 92−93 °C; []D 24 133.2 (c 1, CHCl3, 92% ee); 1H
NMR (500 MHz, CDCl3)  7.75−7.73 (m, 2H), 7.39−7.36 (m, 2H), 3.80 (d, J = 17.0 Hz,
1H), 3.10 (d, J = 17.0 Hz, 1H), 1.65 (s, 3H), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3)
 170.5, 155.2, 137.7, 128.6, 128.0, 96.2, 86.9, 82.4, 43.9, 27.7, 23.5; FTIR (neat) 2982,
2930, 1721, 1587, 1434, 1366, 1311, 1153, 1105, 1005, 913, 817 cm-1; HRMS (EI)
calcd for [M]+ C15H18NO3I 387.0331, found 387.0329; HPLC (Chiralpak AD-H,
hexane/IPA = 90/10, 0.9 mL/min,  = 254 nm) tR = 9.1 min (minor isomer), 14.6 min
(major isomer).
(S)-tert-Butyl 5-methyl-3-p-tolyl-4,5-dihydroisoxazole-5-carboxylate (2e). White
24
1
solid (52 mg, 95%); mp 67−68 °C; []D 167.1 (c 1, CHCl3, 92% ee); H NMR (500
MHz, CDCl3)  7.56−7.53 (m, 2H), 7.21−7.19 (m, 2H), 3.81 (d, J = 17.0 Hz, 1H), 3.13
(d, J = 17.0 Hz, 1H), 2.37 (s, 3H), 1.65 (s, 3H), 1.49 (s, 9H); 13C NMR (125 MHz,
18

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CDCl3)  170.9, 155.9, 140.3, 129.3, 126.6, 126.4, 86.4, 82.3, 44.5, 27.8, 23.5, 21.3;
FTIR (neat) 2984, 2934, 1722, 1432, 1368, 1308, 1260, 1156, 1093, 909, 814 cm-1;
HRMS (EI) calcd for [M]+ C16H21NO2 275.1521, found 275.1521; HPLC (Chiralpak
AD-H, hexane/EtOH = 92/8, 0.9 mL/min,  = 254 nm) tR = 9.6 min (minor isomer),
13.1 min (major isomer).
(S)-tert-Butyl 3-(benzo[d][1,3]dioxol-5-yl)-5-methyl-4,5-dihydroisoxazole-5-
24
carboxylate (2f). White solid (60 mg, 98%); mp 76−77 °C; []D 150.9 (c 1, CHCl3,
91% ee); 1H NMR (500 MHz, CDCl3)  7.27 (d, J = 1.5 Hz, 1H), 7.01 (dd, J = 8.0, 1.5
Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.00 (s, 2H), 3.78 (d, J = 17.0 Hz, 1H), 3.09 (d, J =
13
17.0 Hz, 1H), 1.64 (s, 3H), 1.49 (s, 9H); C NMR (125 MHz, CDCl3)  170.9, 155.6,
149.3, 148.0, 123.3, 121.4, 108.1, 106.4, 101.4, 86.5, 82.3, 44.5, 27.8, 23.5; FTIR (neat)
2982, 2902, 1726, 1507, 1456, 1367, 1302, 1220, 1155, 1103, 1038, 898, 807 cm-1;
HRMS (EI) calcd for [M]+ C16H19NO5 305.1263, found 305.1260; HPLC (Chiralpak
AD-H, hexane/IPA = 90/10, 0.9 mL/min,  = 254 nm) tR = 9.1 min (minor isomer), 15.7
min (major isomer).
(S)-tert-Butyl 3-(furan-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate (2g).
Yellow solid (41 mg, 82%); mp 42−43 °C; []D 23 179.3 (c 1, CHCl3, 91% ee); 1H NMR
(500 MHz, CDCl3)  7.61 (s, 1H), 7.44 (dd, J = 1.5, 1.5 Hz, 1H), 6.76 (dd, J = 1.5, 1.0
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Hz, 1H), 3.69 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 16.5 Hz, 1H), 1.63 (s, 3H), 1.49 (s, 9H);
13C NMR (125 MHz, CDCl3)  170.7, 149.6, 144.1, 142.2, 116.6, 108.0, 86.1, 82.3,
44.7, 27.7, 23.3; FTIR (neat) 3126, 2987, 2936, 1723, 1454, 1369, 1318, 1275, 1152,
1109, 870, 799 cm-1; HRMS (EI) calcd for [M]+ C13H17NO4 251.1158, found 251.1161;
HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.9 mL/min,  = 254 nm) tR = 8.5 min
(minor isomer), 11.5 min (major isomer).
(S)-tert-Butyl 5-methyl-3-(thiophen-3-yl)-4,5-dihydroisoxazole-5-carboxylate
23
(2h). White solid (48 mg, 90%); mp 71−72 °C; []D 184.4 (c 1, CHCl3, 93% ee); 1H
NMR (500 MHz, CDCl3)  7.39 (dd, J = 5.0, 1.0 Hz, 1H), 7.19 (dd, J = 3.5, 1.0 Hz, 1H),
7.05 (dd, J = 5.0, 3.5 Hz, 1H), 3.84 (d, J = 17.0 Hz, 1H), 3.15 (d, J = 17.0 Hz, 1H), 1.65
(s, 3H), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3)  170.5, 151.7, 131.6, 128.4, 128.3,
127.2, 86.8, 82.4, 45.0, 27.7, 23.4; FTIR (neat) 3108, 2990, 2932, 1720, 1439, 1366,
1309, 1202, 1149, 1102, 910, 839, 713 cm-1; HRMS (EI) calcd for [M]+ C13H17NO3S
267.0929, found 267.0931; HPLC (Chiralpak AD-H, hexane/EtOH = 95/5, 0.9 mL/min,
 = 254 nm) tR = 9.1 min (minor isomer), 12.0 min (major isomer).
(S)-tert-Butyl
5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazole-5-
23
carboxylate (2i). White solid (51 mg, 91%); mp 62−63 °C; []D 181.0 (c 1, CHCl3,
1
93% ee); H NMR (500 MHz, CDCl3)  7.27 (d, J = 5.0 Hz, 1H), 6.91 (d, J = 5.0 Hz,
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1H), 3.84 (d, J = 17.0 Hz, 1H), 3.16 (d, J = 17.0 Hz, 1H), 2.46 (s, 3H), 1.64 (s, 3H),
13
1.49 (s, 9H); C NMR (125 MHz, CDCl3)  170.6, 151.9, 139.1, 131.8, 126.0, 125.5,
85.9, 82.3, 46.7, 27.7, 23.3, 16.3; FTIR (neat) 3104, 2976, 2918, 1719, 1438, 1370,
1305, 1154, 910, 843, 740 cm-1; HRMS (EI) calcd for [M]+ C14H19NO3S 281.1086,
found 281.1086; HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.9 mL/min,  = 254 nm)
tR = 5.6 min (minor isomer), 7.4 min (major isomer).
(S)-tert-Butyl 3-phenyl-5-propyl-4,5-dihydroisoxazole-5-carboxylate (2j). White
23
1
solid (47 mg, 81%); mp 50−51 °C; []D 113.3 (c 1, CHCl3, 92% ee); H NMR (500
MHz, CDCl3)  7.67−7.65 (m, 2H), 7.41−7.38 (m, 3H), 3.77 (d, J = 17.0 Hz, 1H), 3.18
(d, J = 17.0 Hz, 1H), 1.94 (t, J = 8.0 Hz, 2H), 1.49 (s, 9H), 1.47−1.35 (m, 2H), 0.97 (t, J
= 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)  170.7, 155.8, 130.0, 129.3, 128.6, 126.6,
89.5, 82.3, 42.2, 39.1, 27.8, 17.2, 14.1; FTIR (neat) 2967, 2928, 2874, 1721, 1446, 1365,
1328, 1230, 1149, 915, 837, 760, 691 cm-1; HRMS (EI) calcd for [M]+ C17H23NO3
289.1678, found 289.1676; HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.9 mL/min, 
= 254 nm) tR = 7.8 min (minor isomer), 13.4 min (major isomer).
(S)-tert-Butyl 5-isopentyl-3-phenyl-4,5-dihydroisoxazole-5-carboxylate (2k).
White solid (51 mg, 80%); mp 98−99 °C; []D 23 104.9 (c 1, CHCl3, 94% ee); 1H NMR
(500 MHz, CDCl3)  7.67−7.65 (m, 2H), 7.41−7.38 (m, 3H), 3.78 (d, J = 17.0 Hz, 1H),
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3.17 (d, J = 17.0 Hz, 1H), 2.02−1.90 (m, 2H), 1.61−1.53 (m, 1H), 1.50 (s, 9H),
1.31−1.20 (m, 2H), 0.90 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3)  170.6,
155.9, 130.1, 129.3, 128.6, 126.6, 89.7, 82.3, 42.1, 34.9, 32.7, 28.1, 27.9, 22.4, 22.3;
FTIR (neat) 2961, 2870, 1720, 1448, 1365, 1300, 1258, 1153, 1066, 916, 758, 690 cm-1;
HRMS (EI) calcd for [M]+ C19H27NO3 317.1991, found 317.1992; HPLC (Chiralpak
AD-H, hexane/IPA = 90/10, 0.9 mL/min,  = 254 nm) tR = 5.5 min (minor isomer), 7.4
min (major isomer).
(S)-tert-Butyl 3-phenyl-5-(3-phenylpropyl)-4,5-dihydroisoxazole-5-carboxylate
(2l). White solid (59 mg, 81%); mp 100−101 °C; []D 23 74.2 (c 1, CHCl3, 96% ee); 1H
NMR (500 MHz, CDCl3)  7.65−7.63 (m, 2H), 7.40−7.37 (m, 3H), 7.28−7.25 (m, 2H),
7.19−7.15 (m, 3H), 3.75 (d, J = 17.0 Hz, 1H), 3.15 (d, J = 17.0 Hz, 1H), 2.66 (t, J = 7.5
Hz, 2H), 1.99 (t, J = 8.0 Hz, 2H), 1.79−1.65 (m, 2H), 1.46 (s, 9H); 13C NMR (125 MHz,
CDCl3)  170.5, 155.8, 141.5, 130.1, 129.2, 128.6, 128.3, 128.3, 126.6, 125.8, 89.4,
82.3, 42.3, 36.4, 35.6, 27.8, 25.5; FTIR (neat) 2976, 2930, 1721, 1597, 1447, 1366,
1297, 1244, 1152, 1128, 915, 747, 690 cm-1; HRMS (FAB) calcd for [M+H]+
C23H28NO3 366.2069, found 366.2073; HPLC (Chiralpak AD-H, hexane/IPA = 90/10,
0.9 mL/min,  = 254 nm) tR = 7.5 min (minor isomer), 11.4 min (major isomer).
(S)-tert-Butyl 5-allyl-3-phenyl-4,5-dihydroisoxazole-5-carboxylate (2m). White
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23
1
solid (49 mg, 85%); mp 39−40 °C; []D 126.0 (c 1, CHCl3, 91% ee); H NMR (500
MHz, CDCl3)  7.67−7.64 (m, 2H), 7.41−7.38 (m, 3H), 5.81−5.73 (m, 1H), 5.22−5.16
(m, 2H), 3.76 (d, J = 17.0 Hz, 1H), 3.23 (d, J = 17.0 Hz, 1H), 2.75−2.67 (m, 2H), 1.50
(s, 9H); 13C NMR (125 MHz, CDCl3)  170.0, 156.0, 131.2, 130.1, 129.1, 128.6, 126.7,
119.9, 88.8, 82.6, 41.5, 41.1, 27.8; FTIR (neat) 2976, 2931, 1725, 1599, 1368, 1283,
1257, 1152, 1001, 907, 759, 691 cm-1; HRMS (EI) calcd for [M]+ C17H21NO3 287.1521,
found 287.1520; HPLC (Chiralpak AD-H, hexane/IPA = 95/5, 0.9 mL/min,  = 254 nm)
tR = 7.1 min (minor isomer), 12.4 min (major isomer).
(S)-tert-Butyl
5-(4-cyanobutyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxylate
(2n). Yellow oil (52 mg, 79%); []D 24 90.8 (c 1, CHCl3, 93% ee); 1H NMR (500 MHz,
CDCl3)  7.66−7.64 (m, 2H), 7.42−7.39 (m, 3H), 3.77 (d, J = 17.0 Hz, 1H), 3.21 (d, J =
17.0 Hz, 1H), 2.37 (t, J = 7.5 Hz, 2H), 2.06−1.94 (m, 2H), 1.77−1.71 (m, 2H),
13
1.65−1.55 (m, 2H), 1.50 (s, 9H); C NMR (125 MHz, CDCl3)  170.2, 155.8, 130.1,
128.9, 128.6, 126.5, 119.2, 88.8, 82.6, 42.6, 35.9, 27.7, 25.1, 22.9, 16.8; FTIR (neat)
2930, 2246, 1724, 1447, 1360, 1255, 1152, 1099, 911, 840, 759, 692 cm-1; HRMS
(FAB) calcd for [M+H]+ C19H25N2O3 329.1865, found 329.1867; HPLC (Chiralpak AD-
H, hexane/IPA = 80/20, 0.9 mL/min,  = 254 nm) tR = 9.6 min (minor isomer), 18.2 min
(major isomer).
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(S)-tert-Butyl
5-[3-(benzyloxy)propyl]-3-phenyl-4,5-dihydroisoxazole-5-
23
carboxylate (2o). White solid (64 mg, 81%); mp 48−49 °C; []D 64.8 (c 1, CHCl3,
1
94% ee); H NMR (500 MHz, CDCl3)  7.65−7.63 (m, 2H), 7.41−7.37 (m, 3H),
7.34−7.30 (m, 4H), 7.29−7.25 (m, 1H), 4.49 (s, 2H), 3.77 (d, J = 17.0 Hz, 1H), 3.51 (t, J
= 6.5 Hz, 2H), 3.20 (d, J = 17.0 Hz, 1H), 2.12−2.02 (m, 2H), 1.78−1.64 (m, 2H), 1.49 (s,
13
9H); C NMR (125 MHz, CDCl3)  170.5, 155.8, 138.3, 130.0, 129.1, 128.5, 128.2,
127.4, 127.4, 126.5, 89.2, 82.3, 72.7, 69.6, 42.2, 33.7, 27.8, 24.2; FTIR (neat) 2980,
2928, 2865, 1720, 1453, 1365, 1332, 1215, 1149, 1126, 916, 841, 762, 733, 691 cm-1;
HRMS (FAB) calcd for [M+H]+ C24H30NO4 396.2175, found 396.2173; HPLC
(Chiralpak AD-H, hexane/IPA = 88/12, 0.9 mL/min,  = 254 nm) tR = 9.8 min (minor
isomer), 16.6 min (major isomer).
(S)-tert-Butyl
5-[3-(tert-butyldimethylsilyloxy)propyl]-3-phenyl-4,5-
23
dihydroisoxazole-5-carboxylate (2p). Colorless oil (78 mg, 93%); []D 56.9 (c 1,
CHCl3, 95% ee); 1H NMR (500 MHz, CDCl3)  7.67−7.64 (m, 2H), 7.41−7.38 (m, 3H),
3.79 (d, J = 17.0 Hz, 1H), 3.64 (dt, J = 6.0, 1.0 Hz, 2H), 3.20 (d, J = 17.0 Hz, 1H),
2.05−2.01 (m, 2H), 1.66−1.61 (m, 1H), 1.58−1.53 (m, 1H), 1.49 (s, 9H), 0.88 (s, 9H),
13
0.04 (s, 3H), 0.03 (s, 3H); C NMR (125 MHz, CDCl3)  170.5, 155.8, 130.0, 129.2,
128.5, 126.5, 89.4, 82.2, 62.5, 42.2, 33.5, 27.8, 27.1, 25.8, 18.1, −5.4; FTIR (neat) 2929,
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2857, 1726, 1447, 1360, 1253, 1151, 1096, 912, 833, 756 cm-1; HRMS (FAB) calcd for
[M+H]+ C23H38NO4Si 420.2570, found 420.2573; HPLC (Chiralpak AD-H, hexane/IPA
= 90/10, 0.9 mL/min,  = 254 nm) tR = 4.3 min (minor isomer), 5.6 min (major isomer).
(S)-tert-Butyl
5-[3-(benzylthio)propyl]-3-phenyl-4,5-dihydroisoxazole-5-
23
carboxylate (2q). White solid (71 mg, 86%); mp 69−70 °C; []D 42.7 (c 1, CHCl3,
1
92% ee); H NMR (500 MHz, CDCl3)  7.65−7.63 (m, 2H), 7.42−7.39 (m, 3H),
7.30−7.27 (m, 4H), 7.24−7.19 (m, 1H), 3.73 (d, J = 17.0 Hz, 1H), 3.69 (s, 2H), 3.13 (d,
J = 17.0 Hz, 1H), 2.46 (t, J = 7.0 Hz, 2H), 2.08−1.96 (m, 2H), 1.72−1.60 (m, 2H), 1.49
(s, 9H); 13C NMR (125 MHz, CDCl3)  170.4, 155.8, 138.3, 130.1, 129.1, 128.7, 128.6,
128.4, 126.9, 126.6, 89.1, 82.5, 42.5, 36.1, 35.9, 31.1, 27.8, 23.5; FTIR (neat) 2987,
2920, 1718, 1598, 1453, 1366, 1296, 1259, 1150, 913, 756, 690 cm-1; HRMS (FAB)
calcd for [M+H]+ C24H30NO3S 412.1946, found 412.1949; HPLC (Chiralpak AD-H,
hexane/IPA = 80/20, 0.9 mL/min,  = 254 nm) tR = 8.5 min (minor isomer), 18.0 min
(major isomer).
(S)-tert-Butyl 5-{4-[(benzyloxycarbonyl)(tert-butoxycarbonyl)amino]butyl}-3-
phenyl-4,5-dihydroisoxazole-5-carboxylate (2r). White solid (88 mg, 80%); mp
72−73 °C; []D 23 42.9 (c 1, CHCl3, 93% ee); 1H NMR (500 MHz, CDCl3)  7.66−7.63
(m, 2H), 7.42−7.38 (m, 3H), 7.37−7.33 (m, 4H), 7.32−7.28 (m, 1H), 7.32−7.28 (m, 1H),
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5.20 (s, 2H), 3.74 (d, J = 17.0 Hz, 1H), 3.63 (t, J = 7.5 Hz, 2H), 3.15 (d, J = 17.0 Hz,
1H), 2.00−1.90 (m, 2H), 1.65−1.59 (m, 2H), 1.48 (s, 9H), 1.45 (s, 9H), 1.42−1.32 (m,
13
2H); C NMR (125 MHz, CDCl3)  170.5, 155.8, 153.7, 152.0, 135.4, 130.1, 129.1,
128.6, 128.4, 128.2, 128.1, 126.6, 89.2, 82.7, 82.4, 68.2, 46.1, 42.2, 36.5, 28.8, 27.8,
27.8, 21.0; FTIR (neat) 2981, 2934, 1752, 1727, 1709, 1455, 1357, 1286, 1152, 1131,
1106, 1069, 907, 755, 690 cm-1; HRMS (FAB) calcd for [M+Na]+ C31H40N2O7Na
575.2733, found 575.2731; HPLC (Chiralpak AD-H, hexane/IPA = 82/18, 0.9 mL/min,
 = 254 nm) tR = 8.9 min (minor isomer), 17.7 min (major isomer).
Large-scale
enantioselective
phase-transfer-catalyzed
cascade
oxa-
Michael‒cyclization reaction for the synthesis of (S)-methiozolin (4).
Hydroxylamine (50 wt% in H2O) (0.75 mL, 12.3 mmol) was added to a mixture of (E)-
tert-butyl 2-methyl-4-(3-methylthiophen-2-yl)-4-oxobut-2-enoate (1i) (1.1 g, 4.1 mmol),
catalyst VIII (259 mg, 0.41 mmol), and cesium carbonate (4.4 g, 13.5 mmol) in MTBE
(41 mL) in one portion. The mixture was stirred at −20 °C for 24 h. The mixture was
quenched by 1 N HCl and extracted with EtOAc. The organic layer was washed with
brine and dried with MgSO4. Filtration, concentration, and purification by flash column
chromatography (SiO2, 8% EtOAc in hexanes) afforded the cascade product 2i in 90%
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DOI: 10.1039/C7OB02722B
yield (1.04 g, 3.7 mmol) and 91% ee as a white solid.
(S)-[5-Methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (3).
Sodium borohydride (419 mg, 11 mmol) was added to (S)-tert-butyl 5-methyl-3-(3-
methylthiophen-2-yl)-4,5-dihydroisoxazole-5-carboxylate (2i) (1.04 g, 3.7 mmol) in
EtOH (12 mL). The mixture was stirred at rt for 24 h. The mixture was quenched by
saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed
with brine and dried with MgSO4. Filtration, concentration, and purification by flash
column chromatography (SiO2, 40% EtOAc in hexanes) provided the alcohol 3 in 95%
23
yield (738 mg, 3.5 mmol) as a white solid. mp 106–107 °C; []D 57.0 (c 1, CH2Cl2);
1H NMR (500 MHz, CDCl3)  7.26 (d, J = 5.0 Hz, 1H), 6.90 (d, J = 5.0 Hz, 1H), 3.72 (d,
J = 12.0 Hz, 1H), 3.57 (dd, J = 12.0, 7.5 Hz, 1H), 3.51 (d, J = 16.5 Hz, 1H), 3.04 (d, J =
13
16.5 Hz, 1H), 2.45 (s, 3H), 2.01 (s, 1H), 1.42 (s, 3H); C NMR (125 MHz, CDCl3) 
152.9, 138.8, 131.8, 126.2, 125.9, 86.8, 67.0, 44.4, 22.4, 16.3; FTIR (neat) 3337, 2931,
2858, 1576, 1435, 1341, 1188, 1075, 939, 901, 754 cm-1; HRMS (EI) calcd for [M]+
C10H13NO2S 211.0667, found 211.0666.
(S)-5-[(2,6-Difluorobenzyloxy)methyl]-5-methyl-3-(3-methylthiophen-2-yl)-4,5-
dihydroisoxazole (4).
Sodium hydroxide (307 mg, 7.7 mmol) was added to (S)-[5-methyl-3-(3-
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methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (3) (738 mg, 3.5 mmol) in
THF (17 mL). The mixture was stirred at 40 °C for 15 min. After addition of 2,6-
o
difluorobenzyl chloride (680 mg, 4.2 mmol), the mixture was stirred at 70 C for 4 h.
After cooling to rt, the mixture was quenched by ice water and extracted with EtOAc.
The organic layer was washed with 1 N HCl and brine, and dried with MgSO4.
Filtration, concentration, and purification by flash column chromatography (SiO2, 7%
EtOAc in hexanes) provided (S)-methiozolin (4) in 77% yield (905 mg, 2.7 mmol) as a
23
1
white solid. mp 43−44 °C; []D 56.1 (c 1, CH2Cl2); H NMR (500 MHz, CDCl3) 
7.29−7.23 (m, 2H), 6.90−6.85 (m, 3H), 4.69 (t, J = 1.0 Hz, 2H), 3.58−3.50 (m, 2H),
13
3.43 (d, J = 16.5 Hz, 1H), 2.98 (d, J = 16.5 Hz, 1H), 2.43 (s, 3H), 1.44 (s, 3H); C
NMR (125 MHz, CDCl3)  161.8 (dd, 1JC-F = 248.7, 7.5 Hz), 152.4, 138.6, 131.8, 130.2
3
2
(dd, JC-F = 10.0, 10.0 Hz), 126.4, 125.7, 113.4 (dd, JC-F = 20.0, 20.0 Hz), 111.2 (dd,
3
2JC-F = 20.0, 6.2 Hz), 85.8, 74.1, 60.7 (t, JC-F = 2.5 Hz), 45.4, 23.0, 16.2; FTIR (neat)
3070, 2933, 2887, 1629, 1595, 1469, 1428, 1330, 1228, 1096, 1053, 863, 789, 710 cm-1;
HRMS (EI) calcd for [M]+ C17H17F2NO2S 337.0948, found 337.0950.
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DOI: 10.1039/C7OB02722B
Conflicts of interest
The authors declare the following competing financial interest(s): The authors are listed
as inventors on a pending patent application related to technology described in this work.
Acknowledgements
This research was supported by the R&D Program of the Ministry of Knowledge
Economy/the Korea Evaluation Institute of Industrial Technology (MKE/KEIT)
(10035240, Development of new herbicides for resistant weeds with mutated genes).
1
13
Electronic supplementary information (ESI) available: Copies of H NMR and C
NMR spectra of all new compounds. Chiral HPLC analysis data of 2a−2r.
Notes and references
1. (a) K, Kaur, V. Kumar, A. K. Sharma and G. K. Gupta, Eur. J. Med. Chem., 2014,
77, 121; (b) R. D. Encarnación, E. Sandoval, J. Malmstrøm and C. Christophersen,
J. Nat. Prod., 2000, 63, 874.
2. (a) P. K. Poutiainen, J. J. Palvimo, A. E. Hinkkanen, A. Valkonen, T. K. Väisänen, R.
Laatikainen and J. T. Pulkkinen, J. Med. Chem., 2013, 56, 1064; (b) S. Castellano,
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