Spiroisoxazoline synthesis via intramolecular cyclization/methylation

Article abstract of DOI:10.1055/s-2006-950302

The synthesis of regioisomeric spiroisoxazolines was achieved through an intramolecular cyclization/methylation reaction of a functionalized 5,5-disubstituted isoxazoline in one reaction vessel. The 5,5-isoxazoline was constructed through a 1,3-dipolar cy

Full text of DOI:10.1055/s-2006-950302

PAPER
3815
Spiroisoxazoline Synthesis via Intramolecular Cyclization/Methylation
Synthesis
i
of Spir
a
oisoxazolin
n
e
ping Xu, Jun Wang, Erick D. Ellis, Ashton T. Hamme II *
Department of Chemistry, Jackson State University, Jackson, MS 39217, USA
Fax +1(601)9793674; E-mail: ashton.t.hamme@jsums.edu
Received 23 June 2006
This paper is dedicated to Dr. Leo A. Paquette for his contributions to the art of synthetic organic chemistry.
1,3-dipolar cycloaddition of an exocylic alkene,9 or other
methods.6b,d The oxidative methods for spiroisoxazoline
synthesis appear to be limited to aromatic systems, and of-
ten require the use of toxic oxidants.7a The 1,3-dipolar cy-
Abstract: The synthesis of regioisomeric spiroisoxazolines was
achieved through an intramolecular cyclization/methylation reac-
tion of a functionalized 5,5-disubstituted isoxazoline in one reaction
vessel. The 5,5-isoxazoline was constructed through a 1,3-dipolar
cycloaddition reaction of an aromatic nitrile oxide and a geminal cloaddition methodology for spiroisoxazoline synthesis is
disubstituted alkene.
usually restricted to the use of saturated ring systems with
an exocyclic double bond as the dipolarophile.9a,b Herein,
Key words: spiro compounds, regioselectivity, cycloadditions,
ring closure, heterocycles
we report a synthetic method for functionalized unsaturat-
ed spiroisoxazoline synthesis that involves the intramo-
lecular cyclization/methylation of a 5,5-disubstituted
isoxazoline in one reaction vessel.
Many synthesized and naturally occurring spiroisoxazo-
lines display biological activity against a variety of dis-
ease states, enzymes, and microorganisms. The
spiroisoxazolines, 11-deoxyfistularin-31 and purealidin
Q2 have been shown to be cytotoxic against cancer, and
other spiroisoxazolines such as zamamistatin,3 aerothion-
in,4 and agelorin5 exhibit antibiotic, antifungal, or antimy-
cobacterial activity (Figure 1). Since these and other
spiroisoxazoline compounds demonstrate such a wide ar-
ray of bioactivities, the synthesis and derivation of this
family of compounds continue to be of interest.6
Previous studies have shown the synthesis of functional-
ized 5,5-disubstituted isoxazolines through a 1,3-dipolar
cycloaddition reaction of aromatic nitrile oxides with 1,1-
disubstituted alkenes.10 The synthesis of the highly func-
tionalized alkene, 3, was achieved in almost quantitative
yield through the alkylation of ethyl 2-(bromometh-
yl)acrylate (2) with ethyl acetoacetate (1) in the presence
of sodium hydride.11 Alkene 3 was then used as a dipo-
larophile for the 1,3-dipolar cycloaddition reaction. The
reaction of a-chlorobenzaldoxime with triethylamine re-
sults in the in situ generation of the nitrile oxide12 which
combines with 3 in a 1,3-dipolar fashion to afford the
highly functionalized 5,5-disubstituted isoxazoline 4 in
high yield as a single regioisomer (Scheme 1).10
A variety of methods exist for the synthesis of functional-
ized carbocyclic spiroisoxazolines. These methods usual-
ly involve the oxidation of an aromatic ring followed by
the intramolecular cyclization of a pendant oxime,7,8 the
Br
MeO
Br
Br
O
Br
O
H
N
H
N
HO
O
N
OMe
O
Br
OH
N
HO
O
Br
11-deoxyfistularin-3
O
O
Br
Br
HO
Br
Br
Br
Br
O
HN
Br
Br
OMe
HO
O
OH
O
Br
Br
H
OH
H
N
MeO
N
N
N
NH
O
O
O
OH
zamamistatin
O
OH
agelorin B
Figure 1 Biologically active spiroisoxazoline natural products
SYNTHESIS 2006, No. 22, pp 3815–3818
x
x
.x
x
.
2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950302; Art ID: M04306SS
© Georg Thieme Verlag Stuttgart · New York

3816
J. Xu et al.
PAPER
O
O
HO
N
OEt
EtO
O
O
Cl
O
1
NaH, THF
98%
OEt
Me
+
N
O
Et3N, CH2Cl2
83%
O
O
4
OEt
O
EtO
Br
O
OEt
3
2
Scheme 1 Synthesis of highly functionalized isoxazoline 4
All chemicals were purchased from commercial vendors and used
without purification. Analytical TLC was performed on precoated
aluminum plates (Merck silica gel 60, F254) and was visualized
with UV light. Products of reactions were purified by flash column
chromatography over Merck Silica Gel 60 (230–400 mesh) using
EtOAc–hexane as eluent. NMR spectra (1H at 250 MHz or 300
MHz, 13C at 62.9 MHz or 75 MHz) were recorded in CDCl3 as the
solvent, and chemical shifts are reported in parts per million relative
to internal solvent signal. IR spectra were taken on a Nicolet Model
Nexus 670 FTIR spectrophotometer.
Decarboxylation of the b-keto ester moiety of 4 with
DMAP afforded the decarboxylated product 5 in moder-
ate yield.13 Intramolecular cyclization and methylation of
5 was achieved in one reaction vessel using sodium hy-
dride in toluene followed by, after the consumption of all
of the starting material, the addition of methyl sulfate. The
spiroisoxazoline 6 was isolated in 35% yield, and its re-
gioisomer, 7, was isolated in 42% yield14 (Scheme 2). The
isolation of two spiroisoxazoline regioisomers results
from the O-methylation of both spiroisoxazoline interme-
diate enolates. The overall yield for the isolation of both
spiroisoxazoline regioisomers is 77% for the two-step,
one-pot process (Scheme 3).15
2-Acetyl-4-methylenepentanedioic Acid Diethyl Ester (3)
NaH (0.56 g, 23 mmol, 60% dispersion in mineral oil) was washed
with anhyd pentane (3 × 3 mL) under N2, which was followed by the
addition of anhyd THF (15 mL). To the ice cooled suspension was
added ethyl acetoacetate (1; 3.0 g, 23 mmol) in THF (5 mL) over a
period of 30 min. After the mixture was stirred for 15 min at r.t., a
solution of methyl 2-(bromomethyl) acrylate (2; 4.50 g, 23 mmol)
in THF (10 mL) was gradually added over a period of 20 min. The
mixture was allowed to warm to r.t. and stirred overnight. The mix-
ture was quenched by the addition of H2O (5 mL) at 0 °C. The aque-
ous layer was extracted with Et2O, and the combined organic layers
were washed with brine, dried (MgSO4), and evaporated under re-
In summary, this study shows the application of the 1,3-
dipolar cycloaddition reaction of a functionalized 1,1-di-
substituted alkene with a nitrile oxide that leads to a high-
ly functionalized 5,5-disubstituted isoxazolines. The latter
was used as a precursor to prepare two regioisomeric
spiroisoxazolines through a two-step one-pot intramolec-
ular cyclization/methylation process.
O
O
MeO
N
O
N
O
O
OEt
Me
NaH, toluene;
(CH3)2SO4
4-DMAP
N
+
OEt
Me
N
O
p-xylene
O
MeO
O
62%
O
6
7
4
5
O
O
OEt
35%
42%
Scheme 2 Synthesis of spiroisoxazoline regioisomers 6 and 7
O
N
O
Na
O
O
N
O
NaH, toluene
+
Na
O
OEt
N
O
Me
O
8
9
5
O
Me2SO4
Me2SO4
6
7
Scheme 3 Intramolecular cyclization of 5 to give enolates 8 and 9
Synthesis 2006, No. 22, 3815–3818 © Thieme Stuttgart · New York

PAPER
Synthesis of Spiroisoxazoline
3817
duced pressure. The crude product was purified by flash column
chromatography over silica gel with (4:1) hexane–EtOAc to afford
3; yellow oil; yield: 5.44 g (98%).
IR (CCl4): 2978, 1723, 1629 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.23–1.34 (m, 6 H), 2.25 (s, 3 H),
2.76–2.93 (m, 2 H), 3.79–3.85 (m, 1 H), 4.14–4.26 (m, 4 H), 5.65
(s, 1 H), 6.21 (s, 1 H).
13C NMR (62.9 MHz, CDCl3): d = 14.1, 14.2, 29.3, 30.6, 58.3, 60.9,
61.5, 127.8, 136.8, 166.4, 169.0, 202.2.
HRMS (EI): m/z calcd for C12H18O5 + Na (M+ + Na): 265.1052;
found: 265.1042.
firmed by TLC on silica gel (4:1 hexanes–EtOAc), dimethyl sulfate
(325 mg, 2.58 mmol) was added, and the mixture was stirred over-
night at r.t. A mixture of H2O (10 mL) and NH4OH (5 mL) was add-
ed sequentially, and the mixture was stirred for 20 min. The organic
layer was washed with H2O (3 × 10 mL) and dried (Na2SO4). The
solvent was evaporated under reduced pressure, and the residue was
purified by column chromatography over silica gel with hexane–
EtOAc (3:1) to afford 6 and 7.
6
Colorless oil; yield: 77.5 mg (35%).
IR (CCl4): 2939, 1674, 1614 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.10–2.20 (m, 1 H), 2.38–2.43 (m,
2 H), 2.98 (d, J = 16.5 Hz, 2 H), 3.76 (s, 3 H), 4.14 (d, J = 16.5 Hz,
1 H), 5.45 (s, 1 H), 7.29–7.41 (m, 3 H), 7.67–7.73 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 25.8, 31.8, 40.5, 56.0, 85.7,
100.6, 126.7 (2 C), 128.6 (2 C), 129.2, 130.1, 156.3, 178.7, 191.6.
HRMS (EI): m/z calcd for C15H16NO3 (M+ + 1): 258.1130; found:
258.1124.
5-(2-Ethoxycarbonyl-3-oxobutyl)-3-phenyl-4,5-dihydroisox-
azole-5-carboxylic Acid Ethyl Ester (4)
A solution of the alkene 3 (1.37 g, 5.00 mmol) and a-chlorobenzal-
doxime (0.80 g, 5.00 mmol) in anhyd CH2Cl2 (30 mL) was treated
with Et3N (0.8 mL, 5.50 mmol). The mixture was stirred at r.t. until
the disappearance of the starting materials, as evidenced by TLC.
After the reaction was complete, the solution was washed with H2O
(5 × 5 mL), the organic layer dried (Na2SO4), and the solvent evap-
orated under reduced pressure. The crude product was purified by
flash column chromatography over silica gel with hexane–EtOAc
(4:1) as eluent to afford 4 as an inseparable mixture of diastereo-
mers; pale yellow oil; yield: 1.65g (83%).
7
Colorless oil; yield: 93.7 mg (42%).
IR (CCl4): 2955, 1738, 1670 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.12–2.25 (m, 1 H), 2.38–2.49 (m,
2 H), 2.77–2.88 (m, 1 H), 3.17 (d, J = 17.5 Hz, 1 H), 3.76 (s, 3 H),
3.93 (d, J = 17.5 Hz, 1 H), 5.49 (s, 1 H), 7.39–7.45 (m, 3 H), 7.67–
7.71 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 33.5, 33.7, 42.5, 56.3, 84.0,
104.1, 126.6 (2 C), 128.7 (2 C), 129.0, 130.3, 156.0, 171.8, 197.9.
HRMS (EI): m/z calcd for C15H16NO3 (M+ + 1): 258.1130; found:
258.1119.
IR (CCl4): 2982, 1731, 1641 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.20–1.35 (m, 6 H), 2.32–2.34 (m,
3 H), 2.45–3.00 (m, 2 H), 3.28–3.36 (m, 1 H), 3.78–3.87 (m, 2 H),
4.11–4.29 (m, 4 H), 7.39–7.44 (m, 3 H), 7.61–7.67 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): d (isomer a) = 13.96, 14.16, 29.4,
34.5, 44.0, 54.8, 61.75, 62.0, 87.0, 126.8 (2 C), 128.7, 128.8 (2 C),
130.5, 156.3, 168.8, 171.05, 201.5; d (isomer b) = 13.99, 14.21,
29.6, 34.7, 44.1, 54.8, 61.82, 62.3, 87.2, 126.8 (2 C), 128.7, 128.8
(2 C), 130.5, 156.4, 169.0, 171.09, 201.7.
HRMS (EI): m/z calcd for C19H24NO6 (M+ + 1): 362.1604; found:
Acknowledgment
362.1620.
We thank the National Institutes of Health (S06 GM 008047-31,
G12RR13459) and the National Science Foundation (HRD-
0401730) for generous financial support.
5-(3-Oxobutyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxylic
Acid Ethyl Ester (5)
A stirred solution of 4 (1.00 g, 2.80 mmol) and 4-DMAP (1.71 g,
14.00 mmol) in anhyd xylene (9 mL) was refluxed overnight. The
mixture was allowed to cool to r.t. and was filtered. After solvent re-
moval in vacuo, the crude product was purified by column chroma-
tography over silica gel with hexane–EtOAc (4:1) as eluent to
afford 4; yellow oil; yield: 0.50 g (62%).
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Synthesis 2006, No. 22, 3815–3818 © Thieme Stuttgart · New York

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Synthesis 2006, No. 22, 3815–3818 © Thieme Stuttgart · New York