Current Organic Chemistry - Volume 4, Issue 5, 2000

Recent applications of the naked sugar methodology are reviewed. General methods have been developed to transform enantiomerically pure 7-oxabicyclo­(2.2.1)heptyl derivatives into rare monosaccharides, carbasugars, into a new doubly-branched imino-dideoxyalditol (iminosugar), into long-chain carbohydrates, C-disaccharides, imino-C-disaccharides and new polyhydroxylated quinolizidines. The methods allow to prepare both enantiomers of a given target with the same ease. Predictable high stereoselectivity of the reactions of the bicyclic chirons adds to the flexibility of the approach that can lead to a large molecular diversity.

Glycobiology is a rapidly evolving field and tackles many phenomena of biomedical importance. Driven by the need to create more efficient methods for the synthesis of complex oligosaccharides, the last few years have seen a major push toward a general approach amenable to solid-phase synthesis. Different strategies have been explored and a host of glycosylating agents have been investigated. New linker systems, different solid support materials and a variety of protective groups have been evaluated. The development of on-resin analytical techniques such as MAS-NMR have greatly facilitated the development of new methods for solid-phase oligosaccharide synthesis. These methodological advances have been demonstrated by preparation of several complex oligosaccharides. As the coupling yields have been improved to 95% and above, the desired products could be obtained in good yield even after seven glycosylations. In addition to single target structures, carbohydrates have generated rapidly increasing interest with respect to sets of diverse, carbohydrate containing molecules. These efforts are of increasing importance for providing molecular tools to elucidate biological processes. While much has been achieved to date, the difficulties encountered in the solid-phase assembly of oligosaccharides underscore the need for the developments of all facets of carbohydrate chemistry. Given the rapid progress in the past eight years, it is conceivable that the synthesis of simple oligosaccharides may soon be automated. Careful investigations into many parameters will eventually allow the synthetic chemist to enable even non-specialists to create important tools for biochemical, biophysical, and medical applications.

Many cellular events such as secretion or proliferation require activation of proteins by calcium ions. Intracellular calcium is mobilized by the formation of the second messenger D-myo-inositol 1,4,5-trisphosphate (InsP3) and subsequent binding to a receptor located on the endoplasmic reticulum. Pharmacological studies of these biological processes have stimulated the search for new ligands of the InsP3 receptor (InsP3R) able to promote or to block the calcium-signaling pathway. As a result, many analogs of InsP3 itself have been prepared by modification of the inositol structure and or modification of the trisphosphate pattern and have been tested for their ability to mobilize calcium. Many weak to full agonists of InsP3R have been disclosed but a synthetic antagonist of InsP3R yet to be discovered. One disadvantage of the use of inositol as starting material is its meso structure and the number of protecting groups manipulation needed to put in place the appropriate phosphate decoration. Some years ago, we reasoned that carbohydrates might be used as scaffolds mimicking the inositol ring to properly present the trisphosphate pattern. During the course of our preliminary investigations the discovery of the adenophostins shed light on a new way to design highly potent calcium mobilizing agents. This review will summarize on advances in the field of the use of carbohydrates as surrogates for inositol and the use of adenophostins as a model.

Microbial carbohydrate structures show a considerable complexity due to the presence of an immense variety in the integral substituents and monosaccharide residues, both regarding structure and position. This severely complicates both the analyses and syntheses of these compounds. This article discusses the synthetic preparation of structures containing some of these intricate structural features. The inner core region of lipopolysaccharides (LPS) of Gram-negative bacteria contains a number of unusual sugars, which are not found elsewhere, the two most abundant are the higher carbon sugars, 3-deoxy-D-manno-2-octulosonic acid (Kdo) and L-glycero-D-manno-heptose (Hep). To prepare core structures, these residues must first be synthesised in a stereospecific manner and then converted to suitable donors and acceptors. Furthermore, must their assembly into oligosaccharide structures be mastered, which is especially difficult with Kdo donors. Recent achievements in the synthesis of core structures are presented including the preparation of Kdo and heptose intermediates, and the construction of complex heptose- and Kdo-containing oligosaccharides, corresponding to structures from Salmonella, Chlamydia, Haemophilus, Neisseria and Moraxella LPSs. Bacterial capsular polysaccharides are frequently built up by phosphodiester linked repeating units. Most often one of the ester bonds is an anomeric linkage. This makes their synthetic formation especially complicated, since not only must the right stereochemistry be introduced but also the lability of anomeric phosphodiester linkages must be considered. Consequently have earlier synthesis of these structures not been possible. In the second part of this article is presented a review of modern achievements in this field, both considering methods and their applications to oligosaccharide synthesis. Synthesised structures from Staphylococcus lactis, Hansenula capsulata, Escherichia coli, Streptococcus pneumonia, Haemophilus influenzae, Neisseria meningitidis, and Leishmania are discussed.