Highly Expedient Ionic Catch-And-Release Oligosaccharide Synthesis through Continuous Flow Reaction

S5.3 Oligosaccharide synthesis II
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:15 to 15:20

Ryan Williams1, Carmen Galan1

1University Of Bristol, Bristol, United Kingdom

Carbohydrates and their preparation continue to be a central focus of research in chemistry and biology, however, despite their ubiquity in living systems their chemical synthesis is non-trivial. Glycosidic bond formation is a crucial step in oligosaccharide synthesis and factors including the choice of leaving group at the anomeric position of the donor, the selection of protecting groups in both donor and acceptor moieties, the solvent system and the choice of promoter must be considered when carrying out the synthesis of glycosides. Emerging strategies to tackle chemical glycosylation utilise innovative techniques that allow for excellent control of stereoselectivity and permit high yields in short reaction times. A good example of this is the advent of expeditious flow methodology as opposed to traditional batch reactions.

The Galan Laboratory developed a novel “catch and release” oligosaccharide synthetic methodology (ICROS) based on ionic supports or “I-Tags”; ionic functional groups covalently linked to sugars [1,2]. I-Tags are advantageous for several reasons. Their highly polar nature in comparison with neutral carbohydrate starting materials and side products allows chromatography-free purification of reactions by simple trituration with appropriate combinations of solvents in a fraction of the time taken for traditional purification methods (Figure 1a). Furthermore, owing to the permanent full positive charge that I-Tags bear, even minute quantities can be easily analysed by mass spectrometry, making reaction monitoring straightforward. Finally, attaching the I-Tag to the sugar via a cleavable linker ensures the I-Tag can be efficiently removed to yield the free, unprotected carbohydrate product. These qualities make the ICROS technique a pragmatic aid for complex oligosaccharide synthesis from simple monosaccharide starting materials. However, the efficiency of this approach is limited by long reaction times for glycosylation reactions and orthogonal deprotections. We sought to tackle this obstacle by utilising continuous flow reactions. Progress in this area will constitute the body of work I would like to present at Eurocarb 2019.

Using a microflow reactor, glycosylation reaction times can be reduced from 16 hours to just 15 seconds with little change in product yield. The system is amenable to a variety of glycosyl donors and acceptors for diverse oligosaccharide synthesis (Figure 1b). Moreover, glycosylation product solution exiting the flow reactor can be fed directly into a deprotection solution, allowing a two-step glycosylation-deprotection with no loss of yield and no need for intermediary purification steps. Rapid purification of I-Tagged products facilitates oligosaccharide assembly quickly and easily, representing a viable strategy for making complex, biologically relevant carbohydrates.

Figure 1a: Ionic tag supported oligosaccharide synthesis strategy.
Figure 1b: Glycosylation reaction using the I-Tag strategy in continuous flow, with chromatography-free purification.

  1. Tran, A. T.; Burden, R.; Racys, D. T.; Galan, M. C. Ionic Catch and Release Oligosaccharide Synthesis (ICROS). Chem. Commun. 2011, 47, 4526-4528.
  2. Sittel, I.; Tran, A. T.; Benito-Alifonso, D.; Galan, M. C. Combinatorial ionic catch-and-release oligosaccharide synthesis (combi-ICROS). Chem. Commun. 2013, 49, 4217-4219.