Elsevier

Tetrahedron Letters

Volume 60, Issue 39, 26 September 2019, 151063
Tetrahedron Letters

A highly efficient and stereoselective cycloaddition of nitrones to N-arylitaconimides

https://doi.org/10.1016/j.tetlet.2019.151063Get rights and content

Highlights

  • High efficient and selective synthesis of new 5-spiroisoxazolidines.

  • High stereoselective 1,3-dipolar cycloaddition of nitrones.

  • New synthetic approach to spirolactones.

Abstract

The 1,3-dipolar cycloaddition of keto- and aldonitrones with N-arylitaconimides proceeds regioselectively giving only 5-spiroisoxazolidines. In the case of aldonitrones the reaction proceeds with high diastereoselectivity. A range of the obtained adducts were subjected to reductive cleavage of the Nsingle bondO bond using zinc powder in acetic acid to give the corresponding spirolactones and 1,3-amino alcohols.

Introduction

The isoxazolidine ring is an important structural part of a wide range of heterocyclic systems possessing valuable pharmacological properties [1], including antiviral [2], antibacterial [3] and antitumor [4] activities. 5-Spiroisoxazolidines have attracted particular interest in recent years [5]. This structural fragment is also found in alkaloids extracted from plants [6]. Highly effective and selective 1,3-dipolar cycloadditions of nitrones with exocyclic double bonds were employed for the synthesis of complex heterocyclic scaffolds containing the spiroisoxazolidine moiety. Many of these products were shown to possess valuable biological properties [7] An undoubted advantage of 1,3-dipolar cycloaddition is the ability to selectively generate up to three new stereocenters in one step without the use of catalysts [8], that makes it indispensable in the synthesis of natural products and their analogues [9].

At the same time, alkylidene succinimides are promising building blocks for the synthesis of complex spiroheterocyclic scaffolds containing the pyrrolidine-2,5-dione fragment. It was shown that their reactions with various 1,3-dipoles: azomethine ylides [10], azomethine imines [11] and nitrile oxides [12] allow construction of the corresponding spirocyclic molecules with high efficiency and diastereoselectivity. However, the regioselectivity of these reactions can be unpredictable and depends on both steric and electronic effects [10], [10]a), [10]b), [10]c), [10]d), [10]e), [10]f), [11], [11]a), [11]b), [12], [12]a), [12]b), [12]c). Recently these reactions have attracted interest due to the promising antibacterial [10a,f], including antimycobacterial [10b,f], and antifungal [10f] activities of the products. Nevertheless, the reactions of these dipolarophiles with nitrones have not been previously studied.

A distinct advantage of isoxazolidines is the possibility of using them as precursors of biologically valuable 1,3-amino alcohols [13], β-lactams [14] and β-amino acids [15]. For example, one of the most universal, simple and inexpensive methods for the reduction of isoxazolidines is the use of zinc powder in acetic acid [16]. In the presence of certain sensitive functional groups or structural fragments, the amino alcohol intermediates can undergo further transformations under the reaction conditions [2]d), [17].

The aim of this work was to investigate the regio- and stereoselectivity of the 1,3-dipolar cycloaddition of keto- and aldonitrones with N-arylitaconimides and transformations of the obtained spiroisoxazolidines under reductive (Zn, acetic acid) conditions.

Section snippets

Results and discussion

Initially, we investigated the regioselectivity of the 1,3-dipolar cycloaddition of N-arylitaconimides 1a-d with N-aryl-C,C-bis(methoxycarbonyl)nitrones 2a-d. The reactions were carried out in dichloromethane at room temperature for three days. It was found that the reactions proceeds regioselectively giving only 5-spiroisoxazolidines 3a-i in good yields (Table 1).

The 1H NMR spectra of the crude reaction mixtures did not show the signals of any other products. The structures of the adducts were

Conclusion

In summary, we have demonstrated that the reactions between the N-arylitaconimides and keto- and aldonitrones proceed regioselectively and in high yields to give 5-spiroisoxazolidines. The regioselectivity is assumed to be determined by steric factors. The reactions with aldonitrones proceed with high diastereoselectivity in most cases. A number of the obtained adducts were reduced under Zn/AcOH conditions. It was demonstrated that this strategy can lead not only to 1,3-amino alcohols, but also

Acknowledgments

NMR, HRMS and XRD studies were performed at the Saint Petersburg State University Center for Magnetic Resonance, Center for Chemical analysis and materials research and X-Ray Diffraction Center, respectively.

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