Elsevier

Carbohydrate Research

Volume 342, Issues 3–4, 26 February 2007, Pages 374-406
Carbohydrate Research

Review
Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

Dedicated to the memory of Professor Nikolay K. Kochetkov
https://doi.org/10.1016/j.carres.2006.10.021Get rights and content

Abstract

The discovery of new methods for stereoselective glycoside synthesis and convergent oligosaccharide assembly has been critical for the area of glycosciences. At the heart of this account is the discussion of the approaches for stereoselective synthesis of glycosides of 2-amino-2-deoxysugars that have emerged during the past two decades. The introductory part provides general background information and describes the key features and challenges for the synthesis of this class of compounds. Subsequently, major approaches to the synthesis of 2-amino-2-deoxyglycosides are categorized and discussed. Each subsection elaborates on the introduction (or protection) of the amino functionality, synthesis of glycosyl donors by introduction of a suitable leaving group, and glycosidation. Wherever applicable, the deprotection of a temporary amino group substituent and the conversion onto the natural acetamido functionality is described. The conclusions part evaluates the current standing in the field and provides a perspective for future developments.

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 (12, 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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      As already stated in the introduction, phosphite and phosphate esters are well-established leaving groups, while few examples are described for anomeric nitrates. Glycosyl nitrates were introduced when Lemieux described the azidonitration of glycals, but at that time, they were just transformed into other leaving groups or, more recently, into simple alkyl glycosides [87–89]. More recently it was demonstrated that they can be used as glycosyl donors under the action of lanthanide triflates, the best results being obtained by the action of Yb(OTf)3 (Scheme 13) [90].

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