Cycloaddition Reactions of Sugar-Based Olefins, Nitrones and Nitrile Oxides: En Route to Saccharidic Spiroisoxazoli(di)nes

Abstract

Isoxazoline and isoxazolidine-containing compounds are privileged structures of interest, notably in synthetic and medicinal chemistry. These heterocycles can be obtained by 1,3dipolar cycloaddition reactions between an olefin and a nitrile oxide or a nitrone. This reaction generates the formation of one C-C and one C-O bond and up to three chiral centers in one step. In the present chapter, we aim to summarize and discuss reports of these cycloadditions on sugar olefins, with a focus on exo-methylene sugars or activated exoglycals, leading with high regio-and stereocontrol to saccharidic spiroisoxazoli(di)nes. Additional examples of cycloaddition reactions involving chiral nitrone, sugar nitrile oxide, sugar nitrone and also two chiral sugar partners will also be discussed. Due to the importance of the spiro structure in several biologically active compounds, these spiroheterocycles can be regarded as spironucleoside analogues, mimics of natural building blocks or multicyclic sugar scaffolds suitable for selective derivatization. Some of them thus showed promising biological properties as antibacterial agents or enzyme inhibitors. Moreover, the labile nature of the N−O bond in the isoxazolidine ring makes it an attractive target for synthetic chemists. The reactivity of this scaffold has therefore been widely studied and the cycloadducts have been converted to other classes of compounds of interest. Examples of the biological relevance and synthetic use and reactivity of these spiro-sugars will be given in this chapter.

[2+2] Cycloadditions of Methylene exo‐Glycals: Synthesis of Glycopyranosylidene‐Spiro‐Azetidine‐2‐ones (β‐Lactams) and Cyclobutanones

“…A regio‐ and stereoselective synthesis of 4′‐thiaspiroacetals was achieved by the inverse electron‐demand hetero Diels‐Alder reaction of exo ‐glycals and 3‐thioxopentane‐2,4‐dione [3] . Spiro‐isoxazolines [4] and ‐isoxazolidines [4a,5] were obtained from exo ‐glycals with nitrile oxides and nitrones, respectively, as 1,3‐dipoles. For the synthesis of C ‐glycosylamino acids, anomeric spiro‐oxazines were prepared by hetero Diels‐Alder reactions of furanoid and pyranoid exo ‐glycals and ethyl‐2‐nitrosoacrylate [6] .…”

Stereoselective Synthesis of Ribofuranoid exo-Glycals by One-Pot Julia Olefination Using Ribofuranosyl Sulfones

“…Exo -glycals are enol ether derivatives of sugars with an exocyclic carbon–carbon double bond . These sugar derivatives have long been used as versatile synthons for a variety of molecules, such as biologically active natural products , and C -glycosyl compounds. , They have also been studied as transition-state analogue inhibitors of sugar-processing enzymes such as glycosidases and glycosyltransferases. ,, Furthermore, they have attracted attention as intermediates in various biosynthetic pathways …”