Construction of novel spiroisoxazolines via intramolecular cyclization/methylation

Article abstract of DOI:10.1016/j.tetlet.2009.07.095

Improved yields for the syntheses of a variety of spiroisoxazolines were achieved through intramolecular cyclization/methylation reactions of functionalized 5,5-disubstituted isoxazolines in one reaction vessel. Aromatic ring containing nitrile oxides and

Full text of DOI:10.1016/j.tetlet.2009.07.095

Tetrahedron Letters 50 (2009) 5516–5519
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of novel spiroisoxazolines via intramolecular
cyclization/methylation
Erick D. Ellis a, Jianping Xu a, Edward J. Valente b, Ashton T. Hamme II a,
*
a Department of Chemistry and Biochemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS 39217, USA
b Department of Chemistry, University of Portland, Portland, OR 97203, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Improved yields for the syntheses of a variety of spiroisoxazolines were achieved through intramolecular
cyclization/methylation reactions of functionalized 5,5-disubstituted isoxazolines in one reaction vessel.
Aromatic ring containing nitrile oxides and disubstituted geminal alkenes reacted in a 1,3-dipolar fashion
to afford the corresponding 5,5-isoxazoline. A comparison of the relative location of the nucleophile and
electrophile on the isoxazoline and two different ester functional groups was performed in order to deter-
mine the best isoxazoline system for the intramolecular cyclization/methylation reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 27 May 2009
Revised 15 July 2009
Accepted 16 July 2009
Available online 22 July 2009
Keywords:
Intramolecular cyclization
Cycloaddition
Regioselectivity
Spirocycles
Heterocycles
1. Introduction
cyclization/methylation of a 5,5-disubstituted isoxazoline10 in
one reaction vessel.
Many synthesized and naturally occurring spiroisoxazolines
exhibit biological activity against a variety of disease states,
microorganisms, and enzymes. The spiroisoxazolines 11-deoxyfi-
stularin-31 and purealidin Q2 have been shown to be cytotoxic
against cancer. Furthermore, other spiroisoxazolines such as
aerothionin,3 aplysinamisines I–III,4 and agelorin5 display anti-
fungal, antibiotic, or antimycobacterial activity (Fig. 1). Since these
and other spiroisoxazoline-containing natural products express
such a wide array of bioactivities, the synthesis and derivatization
of this family of compounds continue to be of interest.6
A number of methods exists for the synthesis of functionalized
carbocyclic spiroisoxazolines. Some of these methods include the
oxidation of an aromatic ring followed by the intramolecular cycli-
zation of a pendant oxime,7,8 the 1,3-dipolar cycloaddition of an
exocyclic alkene,9 or other methods.6b,6d,6e Some oxidative meth-
ods for spiroisoxazoline synthesis appear to be limited to aromatic
systems, and often require the use of toxic oxidants.7a Further-
more, spiroisoxazoline synthesis via 1,3-dipolar cycloaddition is
usually restricted to the use of saturated ring systems with an exo-
cyclic double bond as the dipolarophile.9a,9b Herein, we report a
facile synthetic methodology for the construction of functionalized
unsaturated spiroisoxazolines that involves the intramolecular
2. Results and discussion
A previous report for the syntheses of spiroisoxazolines through
an intramolecular cyclization/methylation methodology used an
isoxazoline where the ester functionality was adjacent to the isox-
azoline, and the attacking enolate was further away from the isox-
azoline11 (Scheme 1). The isolated yield for the intramolecular
cyclization was good when the aromatic ring was unsubstituted.
However, when other aromatic rings were incorporated into the
isoxazoline, the isolated yields dramatically decreased. Our first at-
tempt to improve the intramolecular cyclization yields was to
modify the ester from an ethyl to a methyl ester. Even though ethyl
esters are not very bulky, a decrease in ester size could potentially
be beneficial. Unfortunately, low yields were also obtained with
methyl esters. Other leaving groups were considered, but we
decided to relocate the relative positions of the nucleophile and
the electrophile for the intramolecular cyclization/methylation
reaction as shown in Scheme 2. When the ester was moved away
from a position adjacent to the isoxazoline to a more remote loca-
tion, we believed that the ester carbonyl would be more available
for electrophilic attack by the enolate. In order to test this hypoth-
esis, the appropriate isoxazoline was synthesized.
The syntheses of a variety of isoxazolines was achieved through
the 1,3-dipolar cycloaddition of disubstituted geminal alkenes, 1
and 2,12 with the requisite nitrile oxide. Compounds 3a–d and
* Corresponding author. Tel.: +1 601 979 3713; fax: +1 601 979 3674.
E-mail address: ashton.t.hamme@jsums.edu (A.T. Hamme II).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.095

E. D. Ellis et al. / Tetrahedron Letters 50 (2009) 5516–5519
5517
Br
CH3O
Br
Br
O
Br
OCH3
O
H
N
N
H
HO
O
N
O
N
Br
OH
HO
O
Br
11-deoxyfistularin-3
O
O
Br
Br
Br
Br
Br
N
CH3O
Br
HO
OH
O
N
O
N
Br
Br
H
H
OH
HN
N
N
N
HO
O
O
O
N
H
NH2
O
O
OH
aplysinamisine I
agelorin B
Figure 1. Biologically active spiroisoxazoline natural products.
O
OCH3
N
O
O
N
O
NaH, Toluene;
(CH3)2SO4
+
OCH2CH3
CH3
N
O
OCH3
O
35%
42%
O
Scheme 1. Spiroisoxazoline syntheses from an ethyl ester that is adjacent to the isoxazoline.
R1
O
OCH3
N
O
R1
N
NaH, Toluene;
(CH3)2SO4
R1
O
O
+
OR
N
O
OCH3
O
CH3
R = CH3, CH2CH3
Scheme 2. Spiroisoxazoline syntheses from a methyl ketone that is adjacent to the isoxazoline.
O
4a–d were isolated as a single regioisomer after the respective 1,3-
dipolar cycloaddition of 1 and 2 with the corresponding in situ
generated nitrile oxide13 (Scheme 3). Even though an assortment
of substituted aromatic rings was incorporated into the isoxazo-
line, two different ester functionalities were investigated in order
to compare the relative efficacy of these two esters during the spi-
roisoxazoline ring construction through the intramolecular cycli-
zation/methylation strategy.
When isoxazolines 3a–d, which have a methyl ester, were re-
acted with sodium hydride, intramolecular cyclization ensued,14
and the corresponding enolates were methylated with dimethyl
sulfate to afford the desired regioisomeric spiroisoxazolines 5a–d
and 6a–d11 (Scheme 4). The isolation of two spiroisoxazoline
regioisomers results from the O-methylation of both spiroisoxazo-
line intermediate enolates as shown in Scheme 5,11 and the re-
ported ratios between regioisomers 5 and 6 were based upon
OH
R1
N
Entry Isoxazoline R1
R2 % Yield
R2
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
H
H
Cl
H
H
H
Cl
H
H
OCH3
H
83
68
Cl
R1
R2
R1
O
O
O
66
79
84
88
85
87
RO
CH3
R1
Cl
H
(C2H5)3N, CH2Cl2
OR
N
O
1 R = CH3
2 R = CH2CH3
CH3
OCH3
H
O
3 R = CH3
4 R = CH2CH3
Cl
Scheme 3. Syntheses of 5,5-disubstituted isoxazolines 3 and 4.

5518
E. D. Ellis et al. / Tetrahedron Letters 50 (2009) 5516–5519
R2
R1
R1
R1
R1
O
OCH3
N
N
O
O
NaH, Toluene;
O
R2
R2
+
R1
(CH3)2SO4
OR
N
R1
OCH3
O
O
CH3
O
3: R = CH3
5a-d, from R = CH3
6a-d, from R = CH3
4: R = CH2CH3
5a-d, from R = CH2CH3
6a-d, from R = CH2CH3
Entry Isoxazoline Spiroisoxazoline
R1
H
R2 % Yield
Ratio 5/6
46/54
1
2
3a
3b
5a/6a
5b/6b
H
66
52
H
OCH3
41/59
3
4
5
6
7
8
3c
3d
4a
4b
4c
4d
5c/6c
5d/6d
5a/6a
5b/6b
5c/6c
5d/6d
Cl
H
H
H
Cl
H
86
65
78
72
62
75
46/54
53/47
47/53
57/43
55/45
45/55
H
OCH3
H
Cl
Cl
H
Scheme 4. Syntheses of spiroisoxazolines 5 and 6.
R2
R1
R1
R1
O
O
Na
N
O
N
O
NaH, Toluene
O
R2
R2
+
R1
Na
O
OR
N
O
R1
R1
O
7
8
CH3
O
3: R = CH3
(CH3)2SO4
(CH3)2SO4
4: R = CH2CH3
5a-d, from R = CH3
5a-d, from R = CH2CH3
6a-d, from R = CH3
6a-d, from R = CH2CH3
Scheme 5. Intramolecular cyclization of 3 and 4 to afford regioisomeric enolates 7 and 8.
their respective isolated yields. The spiroisoxazolines arising from
the isoxazoline methyl ester were isolated in moderate to good
yields, but the ethyl ester containing isoxazoline was examined
in order to determine if increased yields of 5a–d and 6a–d could
be realized. Upon subjecting isoxazolines 4a–d to the intramolecu-
lar cyclization/methylation reaction conditions, the isolated yields
of 5a–d and 6a–d were examined. In three cases, spiroisoxazolines
5a–d and 6a–d were isolated in higher yields when the ethyl ester
containing isoxazolines 4a–d were used as the intramolecular
cyclization/methylation substrate. Only spiroisoxazolines 5c and
6c were isolated in higher yields from the methyl ester isoxazoline
precursor (Scheme 4). Structural confirmation of the spiroisoxazo-
lines was obtained through NMR studies, and the structures of 5c
and 6c were further confirmed through single X-ray crystallo-
graphic analysis17 (Fig. 2).
In summary, starting from a disubstituted geminal alkene, spi-
roisoxazolines were synthesized in two steps. After the regioselec-
tive synthesis of the desired 5,5-disubstituted isoxazoline through
Figure 2. Thermal ellipsoid plots for the structures of 5c and 6c.

E. D. Ellis et al. / Tetrahedron Letters 50 (2009) 5516–5519
5519
(c) Masatoshi, M.; Yamada, K.; Hoshino, O. Tetrahedron 1996, 14713; (d)
Murakata, M.; Yamada, K.; Hoshino, O. Heterocycles 1998, 47, 921; (e) Ogamino,
T.; Nishiyama, S. Tetrahedron 2003, 59, 9419.
nitrile oxide-mediated 1,3-dipolar cycloaddition with a disubsti-
tuted geminal alkene,15 regioisomeric spiroisoxazolines were con-
structed through an intramolecular cyclization/methylation
synthetic sequence.16 Structural confirmation of some of the spi-
roisoxazolines was realized through X-ray crystallographic
analysis.
9. (a) Kumar, H. M.; Anjaneyulu, S.; Yadav, J. S. Synth. Commun. 1999, 29, 877; (b)
Reddy, D. B.; Reddy, A. D.; Padmaja, A. Synth. Commun. 1999, 29, 4433; (c)
Manikandan, S.; Jayashankaran, J.; Raghunathan, R. Synth. Commun. 2003, 33,
4063; (d) Bardhan, S.; Schmitt, D. C.; Porco, J. A., Jr. Org. Lett. 2006, 8, 927.
10. (a) Hamme, A. T., II; Xu, J.; Wang, J.; Cook, T.; Ellis, E. Heterocycles 2005, 65,
2885; (b) Yamauchi, M. J. Heterocycl. Chem. 2002, 39, 1013.
11. Xu, J.; Wang, J.; Ellis, E. D.; Hamme, A. T., II Synthesis 2006, 3815.
12. Kalaus, G.; Juhasz, I.; Greiner, I.; Kajtar-Peredy, M.; Brlik, J.; Szabo, L.; Szantay,
C. J. Org. Chem. 1997, 62, 9188–9191.
13. Zamponi, G. W.; Stotz, S. C.; Staples, R. J.; Andro, T. M.; Nelson, J. K.; Hulubei, V.;
Blumenfeld, A.; Natale, N. R. J. Med. Chem. 2003, 46, 87.
Acknowledgments
We thank the National Institutes of Health SCORE and RCMI pro-
grams (3S06 GM 0080407-34S1 and G12RR13459 (NMR and Analyt-
ical CORE facilities)), the MRFN program, and the National Science
Foundation grant DMR05-20415. E.J.V. gratefully acknowledges
the support of the National Science Foundation grant MRI 0618148
and the W. M. Keck Foundation for crystallographic resources.
14. Boers, R. B.; Gast, P.; Hoff, A. J.; De Groot, H. J. M.; Lugtenburg, J. Eur. J. Org.
Chem. 2002, 189.
15. General procedure for 1,3-dipolar cycloaddition:
A solution of the alkene
(3.0 mmol) and the hydroximoyl chloride (3.0 mmol) in 4 mL of
dichloromethane was heated to 50 °C for 10 min. Triethylamine (0.46 mL,
3.3 mmol) was then added dropwise, and the resulting reaction mixture was
heated for an additional 5 min at 50 °C. The reaction mixture was stirred at rt
until the disappearance of the starting materials, as evidenced by TLC. After the
reaction was complete, the reaction mixture was washed with water
(3 Â 4 mL) and brine (4 mL). The organic layer was dried over anhydrous
sodium sulfate, filtered, and the solvent was evaporated under reduced
pressure. Based upon TLC and NMR, no purification was necessary, and the
crude products were used in the subsequent step.
References and notes
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16. General procedure for intramolecular cyclization/methylation: To
a stirred
solution of the isoxazoline (0.87–1.00 mmol) and 5 mL of anhydrous toluene
was added a 60% dispersion of sodium hydride in mineral oil. The reaction
mixture was then heated to 50 °C and stirred overnight. After the
disappearance of starting material, as evidenced by TLC, 1 mmol of dimethyl
sulfate was added to the enolate reaction mixture. The reaction mixture was
then heated to 50 °C, and the mixture was stirred overnight. After the reaction
was complete, NH4OH (1 mL) was added, and the mixture was stirred for
30 min to 3 h. The reaction mixture was washed with water (3 Â 5 mL), and the
organic layer was dried over anhydrous sodium sulfate, filtered, and the
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738659 and 739766, respectively, available free of charge from
www.ccdc.cam.ac.uk/conts/retrieving.html
(or
from
the
Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033).
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