Carbohydrate-spiro-heterocycles

Organic chemistry developed a series of synthetic strategies toward spiro-annulated carbohydrates as potential pharmaceutical drugs or developed new organic synthetic methodologies. The present chapter gives a general overview of the spiro-annulation of carbohydrates at the anomeric position. The main synthetic strategies can be summarized in five paths. Intramolecular cyclizations can be performed through two short tethers with their reactive ends generating the spirocycle or through a single tether reacting at the anomeric position for cyclization. The three other strategies rely on intermolecular reactions with a portion of the spirocycle only in the external substrate or also on the carbohydrate. Radical-mediated cyclization and cycloaddition reactions are the main strategies toward spiro-annulated carbohydrates. A special attention is paid to discussion of the stereocontrol of the anomeric configuration and also to yields in industrial syntheses or biological activities of the molecules. A specific attention is devoted to tofogliflozin and glycogen phosphorylase inhibitors both used as antihyperglycemic drugs and drug candidates, respectively.

Isoxazoline- and isoxazolidine-containing compounds are privileged structures of interest, notably in synthetic and medicinal chemistry. These heterocycles can be obtained by 1,3-dipolar cycloaddition reactions between an olefin and a nitrile oxide or a nitrone. This reaction generates one C–C and one C–O bond and up to three chiral centres 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 exo-glycals, leading to saccharidic spiroisoxazoli(di)nes with high regio- and stereocontrol. Additional examples of cycloaddition reactions involving chiral nitrone, sugar nitrile oxide, sugar nitrone and 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.

This review summarizes the current status of the preparation of spiro-heterocycles fused with a pyranose or furanose carbohydrate skeleton, using free radical chemistry. A variety of heterospiro[m.n]alkane bicyclic structures (m = 3–5, n = 4–6) possessing one, two, or three heteroatoms (N, O, Si, S) have been collected, in addition to three different 1,6,8-trioxadispiro-tetradecane and 1,6,8-trioxadispiro-pentadecane tricyclic systems. C(sp³)–H bond functionalization by 1,5- or 1,6-hydrogen atom transfer (HAT) initiated by C(sp³)-, C(sp²)-, O-, or N-radicals and 5-exo-trig or 6-exo-trig cyclization reactions are the most useful strategies employed for the construction of the heterocyclic rings. The intramolecular HAT promoted by photoexcited monoketones, α-diketones, furanones, and succinimides via a Norrish type II–Yang cyclization process has also been successfully applied.

Various methods for the synthesis of carbohydrate-derived spiroketals and spirocyclic lactones starting from endo- and exo-glycals are discussed. Further conversion of the spiroketals and spirolactones to the natural products is also emphasized wherever applicable.

Derivatives with a double functionalization attract great interest in organic synthesis. The association on the same carbon atom of a nitrile group and a hydroxyl or amine function allows access to promising heterocyclic compounds of particular interest resulting from reactions taking advantage of the electrophilic character of the cyano group and the nucleophilic character of hydroxyl and amino groups. Thus, α-hydroxynitriles (cyanohydrins) or α-aminonitriles represent important classes of organic intermediates. The development of these families in glycochemistry has allowed syntheses of compounds with chain elongations (Kiliani-Fischer synthesis, Strecker synthesis) or even the preparation of chiral building blocks versatile in asymmetric syntheses of biologically active compounds or their intermediates. In this chapter, we summarize the synthesis of quaternized glycoderivatives such as cyanohydrins or glycoaminonitriles and their uses as intermediates to access spiro-heterocycles. Beyond the great structural diversity, stereochemical aspects will also be identified.

Spiroketals are important structural motifs found in diverse natural products, many of which display unique biological activity. Among them, spiroketal phthalane C-glycosides, in which a phthalane ring and sugar unit form a spiroketal framework, have garnered enormous attention from wide research areas because such a fascinating spirocycle motif is found in antibiotic natural products, i.e., papulacandins and their relatives. Moreover, recent reports from pharmaceutical researchers have revealed that spiroketal phthalane C-glycosides are potent drug candidates for type 2 diabetes. Accordingly, the efficient and selective construction of the spiroketal phthalane C-glycoside motif is an important research objective in synthetic organic chemistry. In this chapter, recent advances in the synthesis of spiroketal phthalane C-glycosides will be discussed.