Carbohydrate Synthesis using Fluorous Tags and Separations

Over the last several years, fluorous methods in oligosaccharide chemistry has probably been one of the more active areas of fluorous chemistry with various strategies being employed.  (Visit our website for a fuller explanation of methods to biomolecule synthesis.)

These include:

• Prof. Seeberger (ETH) using fluorous techniques as a complement to solid phase synthesis, either in fluorous capping of undesired sequences or in fluorous tagging.
• Prof. Nicola Pohl (Iowa State Univ.) meanwhile has used a solution phase light-fluorous supported method with FSPE purification as the basis of her synthetic approach to oligosaccharides.
• Prof. Mamoru Mizuno (Noguchi Institute) has utilized a heavy-fluorous supported strategy using FLLE as the separation method.  His group has also used a fluorous mixture synthesis (FMS) strategy for oligosaccharide synthesis which separates the products by F-HPLC.
• Manzoni, Takeuchi, and others have also developed new fluorous tags for carbohydrate synthesis.
• Levery and Siuzdak groups have used fluorous tags in carbohydrate analysis.

Just available as a J. Org. Chem. ASAP paper is another synthetic approach with Prof. Gang Liu at the Institute of Materia Medica in Beijing as the primary author.  The paper describes the synthesis and use of a light fluorous tagged glycosyl donor A, pictured below,which can be reacted with 3 equiv. of  glycosyl acceptor B to form the disaccharide.  The excess B is then easily separated, and recovered, from product C using FSPE.  Conversion of C to a trichloroacetimidate then provides a new glycosyl donor so another saccharide unit can be attached.  All intermediates, and the final detagged product, can be easily purified by FSPE.

So what are the similarities and differences to the methods that have been previously described?  The most obvious similarity is to the work of Prof. Pohl, since both approaches are light fluorous methods using fluorous solid phase extraction (FSPE) as the primary purification method.  It  also has something in common with Seeberger’s solid phase syntheses, since a fluorous TIPS tag is used on the 6-OH.

The most obvious difference from Prof. Pohl’s approach, and that of most others, is that the fluorous tag is on the glycosyl donor rather than the glycosyl acceptor.  This means that the synthesis proceeds in the “opposite” direction.  It’s like the difference between C-termini supported peptide synthesis vs. N-termini supported synthesis.  You get to the same place, but by different means.

The other light fluorous glycosyl donor work in oligosaccharide synthesis that I can think of is that of Prof. Xuefei Huang where they used a fluorous leaving group on the acceptor.  In the Liu work an excess of the acceptor is used relative to the fluorous donor.  In the Huang work, a fluorous donor is used and the non-fluorous tagged product separated from the fluorous by-product.  OK, if this is all getting confusing, I’ve tried to depict the differences below.  In each case, however, the product can be separated from the excess by a simple FSPE.

Take-home message:  fluorous chemistry and carbohydrate chemistry is a good match.