Dr Antony J Fairbanks

Summary of Research Interests

As Synthetic Carbohydrate Chemists we are mainly interested in the problems of stereo- and regioselectivity inherent in the construction of anomeric linkages. Thus, we have several projects centered on oligosaccharide synthesis, glycosylation methodology, and stereocontrolled synthesis of glycomimetics, such as C-glycosides. In addition to the methodological projects listed below, we also have collaborative projects with the Davis group, and the Oxford Glycobiology Institute.

Glycosylation Methodology: Approaches to cis-1,2-Glycosides by Intramolecular Glycosylation

We have a major interest in molecular tethering approaches to cis-1,2-glycosides, for example a-glucosides and b-mannosides. The basic premise is to use an intramolecular glycosylation reaction to control the anomeric stereochemistry. This approach, originally proposed by Ole Hindsgaul, is termed intramolecular aglycon delivery (IAD).

Herein the glycosyl acceptor is temporarily covalently linked to the 2-hydroxyl of the glycosyl donor. Subsequent intramolecular glycosylation then enforces formation of a 1,2-cis-glycosidic linkage with complete control of anomeric stereochemistry. Our initial investigations included development of a one-pot modification(1) of the Hindsgaul approach which allowed both tethering and intramolecular glycosylation to be performed in a single manipulation by the use of N-iodosuccinimide to achieve both steps sequentially(2). Competition reactions reveled that intramolecular glycosylation competes completely over and intermolecular process wherein absolute stereocontrol would not be guaranteed. We also extended the methodology to the synthesis of a-glucosides.

However Hindsgaul type enol ethers derived from 2-O-acetates are not applicable for the glycosylation of hindered secondary carbohydrate alcohols. For this reason we have subsequently introduced the use of the allyl protecting group for IAD(3). The basic reaction sequence involves Wilkinson’s catalyst mediated isomerisation of 2-O-allyl glycosyl donors (thioglycoside or fluoride(4)) to yield 2-O-vinyl ethers. The sequence of tethering of the aglycon (initiated by a source of I⁺).

Allyl IAD has several advantages over other methods of IAD, not least of all the quantitative yields of vinyl ethers produced by the isomerisation step, together with the simplicity of tethering, the stability of mixed acetal intermediates and the lack of requirement for cyclic-4,6-protection to achieve good yields for the glycosylation step. One drawback however is trapping of the oxonium ion produced subsequently to intramolecular glycosylation and this is an issue that we are currently addressing.

We have now successfully applied it to the synthesis of the core Manb(1-4)GlcNAc disaccharide. Current research projects include completion of the core pentasaccharide together with larger N-glycan oligosaccharides, and development of the use of allyl mediated IAD for the synthesis of cis-1,2-amino-glycosides.

Peptide Templated Glycosidic Bond Formation: a New Strategy for Oligosaccharide Synthesis (5)

We are currently investigating a radically new approach to oligosaccharide synthesis, involving the use of templates to allow complete control of regio- and stereochemistry with minimal protecting group manipulations. The principle is to use a combinatorial screen to find particular templates that are capable of effecting the selective formation of particular glycosidic bonds. Since we require templates that can be put together in quantitative yield on the solid phase, and also ones which may display particular a conformational preference, our initial investigations have focussed on the use of templates constructed from a-amino acids.

A study of the outcome of several ‘peptide templated’ glycosylation reactions(6) between aspartate ester bound glycosyl donors and acceptors linked via a variable third amino acid revealed that the stero and regiochemical outcome of the glycosylation reaction was indeed dependent on the identity of the intermediary amino acid.

Molecular modeling studies of the conformational preferences of these tripeptides confirmed a strong conformational preference for the proline containing peptide, which was in agreement with the preponderance for the formation of b-manno disaccharides in this case.

Molecular Modelling of Tripeptides : Low Energy Conformations of DGD and DPD

Since these initial investigations a collaborative project with Dr Ben Davis’ group has been initiated. Our contributions have so far been the development of a second generation approach and combinatorial libraries of linkers are currently being screened in an effort to find particular peptide sequences that produce single glycosylation products in high yield.

Stereoselective Synthesis of C-Glycosides

We have recently developed a new synthetic route which allows access to a wide variety of C-glycosides with complete control of anomeric stereochemistry(7). Esterification of a glycal in which the 3-hydroxyl group is free produces a glycal ester that can then undergo tandem Tebbe methylenation and subsequent Claisen rearrangement to yield a stereodefinied C-glycoside.

Since basically any carboxylic acid may be esterified in this way, and in addition the use of either gluco or allo derived glycals allows access to either the b- or a- C-glycoside respectively, this methodology therefore represents an appealing parallel synthetic approach to small libraries of potentially biologically interesting glycomimetics. In particular ongoing research is applying this methodology to the synthesis of a series of C-glycosyl amino acids and glycopeptides, C-disaccharides, and C-oligosaccharides. All of these C-glycosides will be screened for inhibition of a variety of glycosidases and other carbohydrate processing enzymes.

Glycosylation Methodology

This is also an ongoing area of research for us. We currently have research projects in the following areas.

• Development of new activators for oligosaccharide synthesis
  
  For example we recently introduced(8) the use of N-iodosaccharin (NISac) for the activation of thioglycosides. Interestingly NISac is a selective extremely potent activator of thiophenyl glycosides at low temperature , whereas the usually more reactive thiomethyl glycosides remain unreacted under similar reaction conditions.
  
  
  
• Investigations into the use of electrosynthesis for the rapid assembly of oligosaccharides
  
  These investigations are currently in progress in collaboration with the research group of Professor Richard Compton in the PTCL in Oxford.
  
  
• Mechanistic investigations into glycosylation chemistry
  
  We are currently undertaking investigations into the precise role of the solvent during a number of glycosylation reactions. These investigations were initiated by our recent discovery(9) that NISac mediated glycosylation in acetone as the solvent led to high yields of a-mixed acetal glycosides, wherein a molecule of solvent is trapped out in between glycosyl donor and acceptor.
  
  
  

Our findings indicate that this reaction with acetone is general, and provides a high yielding and efficient route to stereodefined mixed acetal glycosides and disaccharides. It also occurs with other ketone solvents, such as cyclohexanone, and also with the ketone present merely in excess rather than as the solvent. In all cases only a-products have been observed.