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. Author manuscript; available in PMC: 2010 Sep 30.
Published in final edited form as: Tetrahedron Lett. 2009 Sep 30;50(39):5516–5519. doi: 10.1016/j.tetlet.2009.07.095

Construction of Novel Spiroisoxazolines via Intramolecular Cyclization/Methylation

Erick D Ellis a, Jianping Xu a, Edward J Valente b, Ashton T Hamme II a,*
PMCID: PMC2765668  NIHMSID: NIHMS134247  PMID: 20160942

Abstract

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 determine the best isoxazoline system for the intramolecular cyclization/methylation reaction.

Keywords: Intramolecular cyclization, Cycloaddition, Regioselectivity, Spirocycles, Heterocycles

Introduction

Many synthesized and naturally occurring spiroisoxazolines exhibit biological activity against a variety of disease states, microorganisms, and enzymes. The spiroisoxazolines 11-deoxyfistularin-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 antifungal, antibiotic, or antimycobacterial activity (Figure 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

Figure 1.

Figure 1

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Biologically active spiroisoxazoline natural products.

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 cyclization of a pendant oxime,7,8 the 1,3-dipolar cycloaddition of an exocyclic alkene,9 or other methods.6b,d,e Some oxidative methods for spiroisoxazoline synthesis appear to be limited to aromatic systems, and often require the use of toxic oxidants.7a Furthermore, spiroisoxazoline synthesis via 1,3-dipolar cycloaddition is usually restricted to the use of saturated ring systems with an exocyclic double bond as the dipolarophile.9a,b Herein, we report a facile synthetic methodology for the construction of functionalized unsaturated spiroisoxazolines that involves the intramolecular cyclization/methylation of a 5,5-disubstituted isoxazoline10 in one reaction vessel.

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 isoxazoline, and the attacking enolate was further away from the isoxazoline11 (Scheme 1). The isolated yield for the intramolecular cyclization was good when the aromatic ring was unsubstituted. However, when other aromatic rings were incorporated onto the isoxazoline, the isolated yields dramatically decreased. Our first attempt 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 location, we believed that the ester carbonyl would be more available for electrophilic attack by the enolate. In order to test this hypothesis, the appropriate isoxazoline was synthesized.

Scheme 1.

Scheme 1

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Spiroisoxazoline syntheses from an ethyl ester that is adjacent to the isoxazoline.

Scheme 2.

Scheme 2

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Spiroisoxazoline syntheses from a methyl ketone that is adjacent to the isoxazoline.

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 3 a-d and 4 a-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 oxidel3 (Scheme 3). Even though an assortment of substituted aromatic rings was incorporated into the isoxazoline, two different ester functionalities were investigated in order to compare the relative efficacy of these two esters during the spiroisoxazoline ring construction through the intramolecular cyclization/methylation strategy.

Scheme 3.

Scheme 3

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Syntheses of 5,5-disubstituted isoxazolines 3 and 4.

When isoxazolines 3 a-d, which have a methyl ester, were reacted with sodium hydride, intramolecular cyclization insued,14 and the corresponding enolates were methylated with dimethyl sulfate to afford the desired regioisomeric spiroisoxazolines 5 a-d and 6 a-d11 (Scheme 4). The isolation of two spiroisoxazoline regioisomers results from the O-methylation of both spiroisoxazoline intermediate enolates as shown in Scheme 5,11 and the reported ratios between regioisomers 5 and 6 were based upon 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 5 a-d and 6 a-d could be realized. Upon subjecting isoxazolines 4 a-d to the intramolecular cyclization/methylation reaction conditions, the isolated yields of 5 a-d and 6 a-d were examined. In three cases, spiroisoxazolines 5 a-d and 6 a-d were isolated in higher yields when the ethyl ester containing isoxazolines 4 a-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 spiroisoxazolines was obtained through NMR studies, and the structures of 5c and 6c were further confirmed through single X-ray crystallographic analysis17 (Figure 2).

Scheme 4.

Scheme 4

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Syntheses of spiroisoxazolines 5 and 6.

Scheme 5.

Scheme 5

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Intramolecular cyclization of 3 and 4 to afford regioisomeric enolates 7 and 8.

Figure 2.

Figure 2

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Thermal ellipsoid plots for the structures of 5c and 6c.

In summary, starting from a disubstituted geminal alkene, spiroisoxazolines were synthesized in two steps. After the regioselective synthesis of the desired 5,5-disubstituted isoxazoline through nitrile oxide mediated 1,3-dipolar cycloaddition with a disubstituted geminal alkene, regioisomeric spiroisoxazoline were constructed through an intramolecular cyclization/methylation synthetic sequence. Structural confirmation of some of the spiroisoxazolines was realized through X-ray crystallographic analysis.

Acknowledgements

We thank the National Institutes of Health SCORE and RCMI programs (3S06 GM 0080407-34S1 and G12RR13459 (NMR and Analytical CORE facilities)), the MRFN program, and the National Science Foundation grant DMR05-20415. EJV gratefully acknowledges the support of the National Science Foundation grant MRI 0618148 and the W. M. Keck Foundation for crystallographic resources.

Footnotes

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References and Notes

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