ReviewRecent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars
Graphical abstract
Introduction
Elucidation of the exact mechanisms of carbohydrate involvement in pathogenesis of human diseases is difficult due to the complexity and relatively low availability of natural glycostructures. The main conceptual difference between oligosaccharides and other natural biopolymers, that is, proteins and DNA, is in the complexity of the bonds connecting the monomeric units. The glycosidic bond represents a new chirality center and often brings along an obstacle associated with its stereoselective synthesis. The necessity to form either 1,2-cis or 1,2-trans glycosidic linkage with complete stereoselectivity and in high yields is the main reason for which oligosaccharides remain amongst the major synthetic challenges.
Glycosides of 2-amino-2-deoxysugars are present in the most important classes of glycoconjugates and naturally occurring oligosaccharides, in which they are connected to other residues via either 1,2-cis or, more frequently, 1,2-trans glycosidic linkage.1, 2, 3 In particular, 2-N-acetamido-2-deoxyglycosides, most commonly of the d-glucose and d-galactose series, are widely distributed in living organisms as glycoconjugates (glycolipids, lipopolysaccharides, glycoproteins),1 or glycosaminoglycans (heparin, heparin sulfate, dermatan sulfate, chondroitin sulfate, hyaluronic acid),4 and in blood group oligosaccharides5, 6, 7 Aminosugars on cell surfaces play an important role as receptor ligands for protein molecules such as enzymes,8 antibodies,9 and lectins,10, 11 and participate in antibody-antigen interactions.12 As appreciation for the biological importance of 2-amino sugars has increased, so have efforts to develop chemical methods for the synthesis of oligosaccharides containing these residues. Special efforts for the synthesis of glycosyl donors of 2-amino-2-deoxysugars have been focusing on the development of simple, efficient, regio-, and stereoselective procedures.
Generally, a promoter-assisted departure of the leaving group of regular (O-2) glycosyl donors results in the formation of the glycosyl cation, which is stabilized by resonance from O-5 via flattened oxocarbenium ion (Scheme 1a). Hence, the nucleophilic attack is almost equally possible from either the top (trans, β- for the d-gluco series) or the bottom face (cis, α-) of the ring. Even though the α-product is thermodynamically favored (anomeric effect),13 a substantial amount of the kinetic β-linked product is often obtained. Various factors such as temperature, protecting groups, conformation, solvent, promoter, steric hindrance, or leaving groups may influence the glycosylation outcome.14, 15 If the use of a base-labile ester-protecting group is permitted, 1,2-trans glycosides can be reliably prepared with the assistance of a neighboring participating group at C-2.16, 17 These glycosylations proceed primarily via a reactive bicyclic acyloxonium ion intermediate directing the nucleophilic attack mainly to the top face of the ring and allowing stereoselective formation of a 1,2-trans glycoside (Scheme 1b). Many traditional glycosyl donors such as halides, thioglycosides, or O-trichloroacetimidates provide excellent stereoselectivity and high yields.18, 19
Since a vast majority of naturally occurring 2-amino-2-deoxysugars are N-acetylated, from the synthetic point of view, a 2-acetamido-2-deoxy-substituted glycosyl donor would be desirable to minimize protecting group manipulations. For this type of glycosyl donors however, the oxocarbenium ion rearranges rapidly into an oxazoline intermediate (Scheme 1c). Even under harsh Lewis acid catalysis, this highly stable oxazoline intermediate does not exert strong glycosyl donor properties. Although the synthesis of 1,2-trans glycosides is possible with the use of this type of glycosyl donors, the synthesis of 1,2-cis glycosides is a burden. As a matter of fact, the participating nature of the N-acetyl moiety presents an obvious hindrance when the formation of the α-linkage is desired. A minimal requirement for the synthesis of 1,2-cis glycosides would be the use of a C-2 non-participating moiety.
Nowadays, a variety of synthetic approaches to the synthesis of 2-amino-2-deoxyglycosides have been developed and the progress in this area has been previously reviewed.20, 21 These syntheses start from either a glycosamine directly or by introduction of the nitrogen functionality to glycose or glycal derivatives. To this end, various glycosamine donors with modified functionalities have been investigated, in particular, those bearing an N-2 substituent capable of either efficient participation via acyloxonium, but not (2-methyl)oxazoline, intermediate for 1,2-trans glycosylation or a non-participating moiety for 1,2-cis glycosylation. The aim of this account is to summarize the progress toward the establishment of reliable methods for the efficient preparation of differently protected 2-amino-2-deoxyglycosyl donors, their application to oligosaccharide synthesis, and transformation of the protected aminosugars into the natural acetamido derivatives. A particular attention is focused on the recent work.
Section snippets
Synthesis of 2-amino-2-deoxyglycosides from glycals
Glycals (1,2-dehydro sugar derivatives, 1, Scheme 2) are often employed as versatile building blocks in synthetic carbohydrate chemistry.22, 23, 24 Glycals were found to be excellent starting materials for the synthesis of 2-amino-2-deoxysugars by way of N-functionalization at C-2 accompanied by C-1 bond formation. Over the last few decades, a variety of methods have been developed for the nitrogen transfer to glycals (1→2, Scheme 2) and are discussed in the following section.
Synthesis of 2-amino-2-deoxyglycosides via the nucleophilic displacement at C-2
The nucleophilic displacement reaction of appropriately activated derivatives is an indispensable tool for the introduction of substituents into the sugar framework. These reactions proceed via the bimolecular mechanism and result in the inversion of configuration. The efficiency of the displacement strongly depends on the site of substitution, the nature of the nucleophile, the leaving group, the polarity of the solvent, and other factors. Other common reactions of this class include
Synthesis of glycosides from 2-amino-2-deoxysugars via the introduction of an amine protecting group
As mentioned earlier, naturally occurring 2-amino-2-deoxy glycopyranosides are often N-acetylated and are linked via 1,2-trans-glycosidic linkages. The use of N-acetylated donors, however, is often impractical. On the one hand, glycosidation of such donors often leads to the formation of relatively unreactive oxazoline intermediate that often remains as a major by-product. On the other hand, high nucleophilicity of the lone pair of electrons on nitrogen of the acetamido group also presents a
Summary
The discovery of new methods and strategies for stereoselective glycoside synthesis and convergent oligosaccharide assembly has been critical for the area of glycosciences. Herein, we discussed only a fairly narrow topic dealing with the synthesis of O-glycosides of 2-amino-2-deoxysugars. As evident from the recent accomplishments, in spite of the recent progress, no universal approach for the synthesis of this class of compounds has yet been developed. A variety of excellent participating
Acknowledgment
The authors thank the American Heart Association (AHA0660054Z) for the financial support of this work.
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