Olefin metathesis in glycobiology: new routes towards diverse neoglycoconjugates
Introduction
Synthetic research in carbohydrate chemistry is increasingly aimed at the design and preparation of artificial glycoconjugates (constructs that contain structural and functional elements of naturally occurring glycoconjugates) rather than the natural compounds themselves. The reason for this shift in attention is twofold. First, there is no general synthetic protocol for the preparation of complex glycoconjugates and oligosaccharides. This situation is unlikely to change in the near future, despite considerable progress in past decades exemplified by recent exciting results in the areas of chemoselective and automated solid-support oligosaccharide synthesis 1., 2.. The sheer structural diversity encountered in natural oligosaccharides and glycoconjugates, combined with the challenges associated with the regioselective and stereoselective formation of interglycosidic linkages simply frustrates the development of general oligosaccharide synthesis protocols. Second, there is a growing realisation that to study and manipulate biological processes involving carbohydrates, the natural compounds are not necessarily required. Artificial carbohydrate-containing constructs, termed neoglycoconjugates, can be tailor-made to display similar or even better biological properties [3].
An important factor governing the development of neoglycoconjugates is the finding that many biological interactions involve multiple carbohydrate entities, rather than a single one [4]. Consequently, many research efforts in contemporary carbohydrate chemistry aim to develop strategies that enable the linking of carbohydrates to a certain core, not through natural interglycosidic linkages, but through bonds that can be more easily installed. Moreover, these linkages may be made more stable towards enzymatic degradation, and be designed to afford regiochemically and stereochemically defined compounds. Examples of these strategies have been reported in the preparation of synthetic mimics of natural glycoconjugates (for instance neoglycopeptides), in the generation of artificial carbohydrate-based receptors, in the preparation of glycopolymers and in the immobilisation of carbohydrates on microtiter plates. Several reviews covering this area of research have been published recently 5., 6..
One of the most intensively studied and applied transformations in organic chemistry of the past decade is the transition metal catalysed olefin metathesis. Thanks to the research efforts of many groups, primarily those of Schrock and Grubbs 7., 8., homogeneous catalyst systems are available that display high functional group tolerance, are highly selective in their reactivity and can be employed under mild reaction conditions. The scope of the various metathesis events, mechanistic considerations and developments in catalyst design have been reviewed extensively over the years 9., 10., 11.. Several distinct metathesis events and catalyst types (1–6) that are relevant to this review are depicted in Figure 1. Briefly, cross-metathesis (CM) comprises the formation of a 1,2-disubstituted alkene and ethylene from two functionalised alkenes. Ring-closing metathesis (RCM) represents the cyclisation of a diene, whereas cyclic alkenes can undergo ring-opening metathesis (ROM) in the presence of a linear alkene, or ring-opening metathesis polymerisation (ROMP) in the absence of one. Other useful metathesis transformations are the CM- and RCM-mediated formation of 1,3-dienes from alkenes and alkynes.
Carbohydrates have been used extensively in olefin metathesis. The metathesis-mediated transformation of carbohydrates into natural products and carbohydrate mimics has been covered in several reviews 12., 13. and fall outside the scope of this report. This paper aims at giving an overview of the application of olefin metathesis in the synthesis of neoglycoconjugates. In particular, the following classes of compounds will be discussed: neoglycopolymers, glycoclusters, neoglycopeptides, neoglycolipids and oligosaccharide analogues.
Section snippets
Neoglycopolymers
The pioneering work of the group of Grubbs in the field of olefin metathesis has, among many other exploits, resulted in the first ruthenium-mediated ROMP towards neoglycopolymers. Having developed a living polymerisation methodology for strained alkenes such as norbornene [14], it was reasoned that attachment of a monosaccharide unit to the monomer (for instance 7a, Figure 2) would lead to a neoglycopolymer (8a) after ROMP [15]. It was found that the characteristics of the resulting polymer
Glycoclusters
As part of an elegant synthesis of a novel type of glycocluster, the group of Roy [21••] reported the CM of a variety of C-glycosides with protected allylamine. As depicted in Figure 3, acetylated allyl-C-galactoside 19 was reacted with benzyloxycarbonyl-protected allylamine under the influence of catalyst 5, to give CM product 20 in moderate yield. The amine in 20 was then functionalised with an ethynylbenzoyl function for subsequent dimerisation to give adduct 22. In a spectacular
Neoglycopeptides
The CM of alkene-containing carbohydrates and amino acids has attracted much attention in recent years. Important reasons for this interest are that the resulting glycosyl amino acids can easily be built into peptide-like glycoclusters or glycopeptides, and in the case of C-glycosyl-alkenes, metabolically stable glycopeptide analogues can be generated. Several examples of the latter category were reported by the group of Roy [21••]. For instance, a CM reaction between C-mannoside 29 (Figure 4)
Neoglycolipids
The construction of lipophilic macrocyclic lactones (Figure 5) from carbohydrate dienes and their ensuing saponification to afford acetogenin analogues was studied by Gesson and co-workers [27]. They found that, depending on the length of the fatty acid tail in 39, competitive RCM and CM events occurred, leading to lactone 40 and homodimer 41. Methanolysis of this mixture afforded the target high-carbon sugars 42. In a CM event, compound 43 was prepared starting from the appropriate allyl
Oligosaccharide analogues
As early as 1994, Descotes and co-workers reported [30] the CM-mediated transformation of glucosides containing a terminal olefin into bolaamphiphiles 46a–c (Figure 6). This pioneering work, which comprises the first literature example of the implementation of olefin metathesis in carbohydrate chemistry, formed the basis for later exploits by Roy, for instance, the transformation of alkenyl lactosides into the corresponding symmetric pseudo-oligosaccharides [31]. In line with these results,
Conclusion and outlook
The examples presented here comprise the olefin metathesis-mediated construction, starting from functionalised carbohydrates, of a wide array of neoglycoconjugates. Despite the exciting structural and functional features encountered in the compounds described above, useful applications in biology and medicine are still limited. With the continuous expansion of the functional entities incorporated in neoglycoconjugates, this situation will probably change in the near future. In this respect, an
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
The authors thank the Netherlands Organisation for Scientific Research (NWO-CW) for financial support.
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