The synthesis of oligosaccharides is not easy when compared to to other oligomeric biomolecules such as oligonucleotides and peptides. There’s a number of reasons for this, but primarily it comes down to one thing: complexity. For example, DNA is made from four different monomers which are connected by phosphates through the 5′ and 3′ hydroxyls. Peptides are formed from 20 different monomers connected by amide bonds between the C and N terminus. Oligosaccharides, on the other hand, are produced from dozens of different monomers connected by acetal bonds forming a stereocenter which needs to be controlled. On top of that, oligosaccharides need not be linearly attached like peptides and oligonucleotides, but are often branched. With all of this complexity, it’s perhaps not surprising that development of methods for their synthesis and purification have remained an area of intense research for a long time.
Count fluorous methods among those that have been tried and for the most part, very successfully. For a brief summary of some of the fluorous strategies that have been employed, click here.
The Huang group now adds another method; fluorous catch and release. Their strategy, described in this Eur. JOC paper, is to use a one-pot synthesis to form an oligosaccharide with a reactive functional group linker. A fluorous reagent which reacts with the linker is added to fluorous functionalize the desired oligosaccharide, which is then separated from all the non-fluorous junk using fluorous solid phase extraction (FSPE). The linker is cleaved to release the oligosaccharide from the fluorous tag and a second FSPE used.
The implementation of this strategy requires a linker and fluorous reagent combination that is a) compatible with oligosaccharide synthesis, b) selective for reaction with the linker only, and c) readily cleavable without altering the oligosaccharide. The authors first tried to use an azide as the linker and a fluorous phosphine as the reagent, but found that aza-ylide was not stable to FSPE. They then tried an aldehyde-hydrazine combination, but discovered that the aldehyde was not stable enough. Substituting the aldehyde with a ketone and modifying the hydrazine, however, led to a suitable linker-reagent pair. Once they had found the right combination, they then demonstrated the usefulness of their methodology by preparing several oligosaccharides, including LewisX, a branched trisaccharide which was prepared in 62% yield. The completed oligosaccharide was isolated from the reaction mixture using FSPE only with no chromatography to provide material that was pure by 1H NMR.
Given all the ways fluorous techniques have been employed in oligosaccharide chemistry, it’ll be interesting to see how the fluorous catch and release strategy is viewed and used within the carbohydrate synthesis community.