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The importance of glycosidase inhibitors and especially the bicyclic molecules has led to design and assessment of many analogs of naturally occurring molecules. This review focuses on the synthesis and enzyme inhibitions of a few selected (synthetic or non-naturally occurring) molecules that have been reported in the last decade, which allow one to draw some connection between varying the structural features and their effect on glycosidase inhibitions. It is expected that further improvements based on these features could lead to improved inhibitors.

An expedient one-step synthesis of 2-iodoglycals and 2-bromoglycals from glycals using NIS/AgNO3 and NBS/AgNO3 as reagent systems has been developed. The utility of these 2-haloglycals has been demonstrated by converting them into 2C-branched glycals via the Heck coupling reaction. Ferrier reaction of tri-O-acetyl-2-iodoglycals followed by Heck coupling reaction with methyl acrylate leads to 2C-branched O-glycosides.

[Reaction: see text]. The biological significance of oligosaccharides and glycoconjugates is profound and wide-ranging. For example, the mucins have attracted attention because of their role in fundamental cellular processes such as fertilization, parasitic infection, inflammation, immune defense, cell growth, and cell-cell adhesion. Increased expression of mucins is implicated in malignant transformation of cells. Antifreeze glycoproteins also are of interest because they are important for the survival of many marine teleost fishes that live in polar and subpolar waters. The synthesis of glycoconjugates requires methods for glycoside bond formation, the most difficult aspect of which is the assembly of monosaccharide building blocks. This Account discusses a valuable addition to the repertoire of methods for glycoconjugate synthesis: an approach that involves 2-nitroglycal concatenation. For a long time, methods for glycosylation via glycosyl donor generation required either an anomeric oxygen exchange reaction or anomeric oxygen retention. In the case of an anomeric oxygen exchange reaction, activation of the glycosyl donors demands a promoter in at least equimolar amounts. However, anomeric oxygen retention, such as base-catalyzed formation of O-glycosyl trichloroacetimidates, can be activated by catalytic amounts of acid or Lewis acid. Alternatively, glycals, which are readily available from sugars, can be an attractive starting material for glycoside bond formation. Their nucleophilic character at C-2 permits reactions with oxygen, nitrogen, and sulfur electrophiles that under high substrate stereocontrol generally lead to three-membered rings; ring opening under acid catalysis furnishes the corresponding glycosides, whichdepending on the electrophile Xare also employed for 2-deoxyglycoside synthesis. Glycals also can be transformed into derivatives that have at C-2 an electron-withdrawing group and are amenable to Michael-type addition. A good example are 2-nitroglycals. In this case, glycoside bond formation is achieved under base catalysis and leads to 2-deoxy-2-nitroglycosides. These intermediates are readily converted into 2-amino-2-deoxyglycosides, which are constituents of almost all glycoconjugates. This 2-nitroglycal concatenation has been extensively investigated with 2-nitrogalactal derivatives. When alcohols are used as nucleophiles and strong bases used as catalysts, the result is primarily or exclusively the alpha-galacto-configured adducts. Some studies show that weaker bases may lead to preferential formation of the beta-galacto-configured products instead. The reaction was very successfully extended to other nucleophiles and also to other 2-nitroglycals that undergo base-catalyzed stereoselective Michael-type additions. Thus, 2-nitroglycals are versatile synthons in glycoconjugate and natural-products synthesis, and it is foreseeable that many more applications will be based on these readily available and highly functionalized skeletons.

Perchloric acid supported on silica gel acts as an excellent reagent system in converting glucals into 2,3-unsaturated-O-glucosides in good to excellent yields in short reaction time with good alpha selectivity. Primary, secondary, and allylic alcohols, phenols, and thiols react with 3,4,6-tri-O-acetyl glucal with equal ease. In addition to this, a chiral furan diol is obtained from unprotected D-glucal or D-galactal in good yields.

The chemistry for the synthesis of glycosphingolipids has been greatly advanced in the last two decades, and now almost any compound of any structural complexity can be prepared. The methodology is based on the development of efficient glycoside bond formation strategies in order to obtain the oligosaccharide moiety, on the synthesis of useful sphingosine intermediates, and finally on their successful ligation in order to provide neutral as well as acidic glycosphingolipids (i.e. gangliosides). Also enzymatic approaches towards this goal have been investigated. Recent conformational and biological studies exhibit a rapidly growing understanding of the physical properties and the importance of glycosphingolipids which is essentially based on the great synthetic achievements discussed in this review.

A reagent system comprising tetrabutylammonium nitrate-trifluoroacetic anhydride-triethylamine has been developed for the synthesis of 2-nitroglycals from various protected glycals. The base-catalyzed Ferrier rearrangement on tri-O-acetylated 2-nitroglycals has been reported for the first time. Reactivity of these nitroacetates and associated selectivity has been examined, and some of the products have been converted into 2,3-diamino-2,3-dideoxyglycosides and methyl N-acetyl-D-lividosaminide.

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