Fluorous Protecting Groups in Oligosaccharide Synthesis

The regular reader of F-Blog will know that the fluorous-assisted synthesis of oligosaccharides is one of the best applications of fluorous techniques.  Fluorous tags and separations, primarily fluorous solid phase extraction (FSPE), have been used in a number of different ways for the preparation of oligosaccharides including fluorous supported synthesis, one-pot catch and release approaches, and chemoenzymatic syntheses.  The orthogonality of fluorous separations to chromatographic methods is really highlighted by the number of different strategies used, since oligosaccharide chemistry can involve intermediates of vastly different polarities depending on synthetic strategy and degree and type of hydroxyl protection.

A recently available paper form Takahashi and co-workers at the Tokyo Institute of Technology report the preparation of a new fluorous protecting group and it’s use in oligosaccharide synthesis.  Aside from the new protecting group, the approach, shown below, that the researchers used was somewhat different from previous fluorous carbohydrate synthesis strategies.  In this case the authors used a one-pot synthesis with the fluorous tag on one of the monomer units.  Huang’s catch and release one-pot strategy used untagged monomers and instead fluorous tagged the full length oligosaccharide.  In each case, however, the full length oligosaccharide was separated from the other reaction components by FSPE.

The authors first fluorous tagged a protected glucopyranoside with the fluorous phenylether and went through their deprotection sequence (Birch reduction of the phenylether followed by TFA mediated hydrolysis) to demonstrate that the fluorous tag did not effect the reactivity of the protecting group.  They then prepared a disaccharide and a trisaccharide through activation of the glycosyl donor and sequential addition of glycosyl acceptors.  Once the full length oligosacchride was prepared gel permeation chromatography (GPC) and FSPE were used to purify the protected fluorous tagged oligosaccharide.  Deprotection followed by another FSPE then provided the final trisaccharide in very good yield. 

As usual there are some important points to note in this paper.  First, the fluorous tag has minimal effect on the reactivity of the protecting group.  The authors were able to simply employ the fluorous version of the phenethyl ether tag based on their previous work without any modification of the reaction conditions.  Next is the use of GPC purification.  The authors do not mention why this was necessary, but it does point out that a fluorous tag does not preclude the use of alternate purification methods if needed.  Other methods, such as solid phase, may have required detagging and retagging.  Then theirs the ability to monitor the reaction which is absolutely critical in a one-pot synthesis like this.  You don’t want to add the next set of reagents until the first reaction is complete.  Fluorous tags allow for full reaction monitoring using standard techniques.

Just another demonstration of the versatility and utility of fluorous technologies.

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