Glycals (or usually their O-substituted derivatives) are readily converted into 2,3-unsaturated glycosyl compounds with O-, C-, N-, S- or otherwise linked substituents at the anomeric position. These products have been found to be useful for a range of synthetic purposes. In particular, the C-glycosidic compounds have served as readily available starting materials for the preparation of useful non-carbohydrate compounds. While these allylic rearrangement processes are usually conducted under the influence of Lewis acid catalysts, adaptations that involve activation of the allylic substituents of the starting glycals as leaving groups under neutral conditions have been developed. General features of the reactions are described as well as applications in synthesis and extensions of the basic processes.

Substitution-with-Allylic-Rearrangement Reactions of Glycal Derivatives

C-branched carbohydrates are of current interest for glycochemistry, are widely found in nature and serve as important subunits in many antibiotics, bacterial polysaccharides and macrolides. Among C-functionalized saccharides, 2-C-branched carbohydrates represent challenging structures for synthetic chemists, since in contrast to C-glycosides they are not easily accessible from glycosyl bromides or other simple precursors. In this perspective we want to summarize recent approaches to 2-C-branched carbohydrates over the past fifteen years. The two main strategies are based on ring-opening of 1,2-cyclopropanated carbohydrates by various reagents, as well as radical additions to glycals and further transformations, developed in our group. Both methods are characterized by high stereoselectivities and good yields and give access to a broad variety of functionalized carbohydrate 2-C-analogs.

Recent advances in the stereoselective synthesis of carbohydrate 2-C-analogs.

Glycals, 1,2-unsaturated sugar derivatives, are versatile starting materials for the synthesis of natural products and the generation of novel structural features in Diversity Oriented Synthesis (DOS). The versatility of glycals in synthesis emanates, among others, from the presence of the ring oxygen and the enol-ether type unsaturation, the different types of stable conformations they can adopt depending on the nature of the protecting groups present and the ease with which the protecting groups of the three hydroxy groups could be tailored to suite for a desired manipulation. This review summarizes the literature on the different transformations of the endo glycals into biologically relevant compounds such as chromans, thiochromans, chromenes, thiochromenes, peptidomimetics, bridged benzopyrans etc., as well as on the use of glycals as chiral building blocks for the synthesis of various natural products such as aspicilin, reblastatin, diospongins, decytospolides, osmundalactones, paclitaxel, isatisine, D-fagomine, and spliceostatin, reported post 2014.

Versatility of glycals in synthetic organic chemistry: coupling reactions, diversity oriented synthesis and natural product synthesis

Selective reactions of transition-metal-generated radicals

2-C-malonyl carbohydrates were synthesized in only few steps and high yields by radical additions of malonates to glycals. For the first time, the undesired formation of nitrates was completely suppressed with anhydrous cerium ammonium nitrate (CAN) as oxidizing agent. A coherent explanation for the high stereoselectivities of the additions to gluco-configured glycals was provided by variation of the substituents in the 3-position. We established steric effects for the face selectivity, and electronic effects strongly influence the reactivity of the double bonds. The scope and limitation of transition-metal-mediated radical reactions in the synthesis of 2-C-branched carbohydrates was thoroughly investigated. Thus, unsaturated disaccharides and benzyl-protected glycals were used as substrates for the first time. Finally, the 2-C-malonyl carbohydrates were transformed into various products by decarboxylation, saponification and reduction, which afforded interesting precursors for C-disaccharides. In this paper we describe the syntheses of more than 40 new 2-C-analogues of carbohydrates, which were isolated in high yields in analytically pure form. Therefore, the transition-metal-mediated radical addition of malonates to glycals offers a simple and convenient entry to such important carbohydrate derivatives.

Convenient syntheses and transformations of 2-C-malonyl carbohydrates.

On treatment with boron trifluoride–diethyl ether in benzene solution, tri-O-acetyl-D-glucal dimerises, and from the products the crystalline C–C linked disaccharide derivative 1,3,4,6-tetra-O-acetyl-2-C-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranosyl)-2-deoxy-β-D-glucopyranose has been isolated. Dimerisation is believed to occur by the trans-addition of one molecule of 1,4,6-tri-O-acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranose to the double bond of another, and in agreement with this, evidence has been obtained that tri-O-acetyl-D-glucal initially rearranges in the presence of the catalyst (or thermally) to give mainly the 2,3-unsaturated isomer.

N. Prasad

Papers

Unsaturated carbohydrates. Part XI. Isomerisation and dimerisation of tri-O-acetyl-D-glucal