Synthesis of Spironucleosides: Past and Future Perspectives

Abstract

Spironucleosides are a type of conformationally restricted nucleoside analogs in which the anomeric carbon belongs simultaneously to the sugar moiety and to the base unit. This locks the nucleic base in a specific orientation around the N-glycosidic bond, imposing restrictions on the flexibility of the sugar moiety. Anomeric spiro-functionalized nucleosides have gained considerable importance with the discovery of hydantocidin, a natural spironucleoside isolated from fermentation broths of Streptomyces hygroscopicus which exhibits potent herbicidal activity. The biological activity of hydantocidin has prompted considerable synthetic interest in this nucleoside and also in a variety of analogues, since important pharmaceutical leads can be found among modified nucleoside analogues. We present here an overview of the most important advances in the synthesis of spironucleosides.

Glucopyranosylidene-spiro-benzo[b][1,4]oxazinones and -benzo[b][1,4]thiazinones: Synthesis and Investigation of Their Effects on Glycogen Phosphorylase and Plant Growth Inhibition

“…General Procedure III for the Synthesis of Spiro{1′,5′anhydroglucitol-1′,2-benzo[b] [1,4]oxazinones}. In a round-bottom flask, 30 mg of Pd/C (10 wt %) was suspended in dry EtOAc (5 mL) under Ar atmosphere.…”

“…In conclusion, synthetic methods were elaborated for new anomeric spirocycles, namely, spiro{1′,5′-anhydroglucitol-1′,2benzo[b] [1,4]oxazinones} and spiro{1′,5′-anhydroglucitol-1′,2-benzo[b] [1,4]thiazinones}. Enzyme kinetic assays with rabbit muscle glycogen phosphorylase b showed either no or weak inhibition (max 28% at 625 μM).…”

“…Sugar anomeric spirocycles are an important class of compounds; many of them display important biological activities. Although these compounds are mostly synthetic, some natural representatives are also known, such as hydantocidin with herbicidal activity and the antifungal agent papulacandin. , …”

“…Although these compounds are mostly synthetic, some natural representatives are also known, such as hydantocidin with herbicidal activity and the antifungal agent papulacandin. 1,2 Numerous glucopyranosylidene-spiroketals and -spiroaminals have been synthesized and tested as antidiabetics (Table 1), as either inhibitors of glycogen phosphorylase (GP) 3−5 or those of sodium-dependent glucose cotransporters (SGLT2). 5−7 Glucopyranosylidene-spiro-hydantoin 8 (A), -thiohydantoin 9,10 (B), -isoxazolines 11 (C), -oxathiazolines 12 (D), and sulfamides 13 (E) are among the most effective catalytic site inhibitors of GP with low-micromolar and submicromolar activity.…”

“…32 Plants also exude these chemicals into the soil, 33 which suppresses the germination and development of weeds. 34 The aim of this research was to synthesize new spiro{1′,5′anhydroglucitol-1′,2-benzo[b] [1,4]oxazinones} and -1,4-thiazinones (Figure 1) to enlarge the family of spirocyclic GP inhibitors with six-membered heterorings. Furthermore, because these target compounds are analogues of the natural product HBOA and DIBOA glucosides, we also wished to test their effect on plant physiology, particularly on germination.…”