Fluorous Supported Synthesis of Teichoic Acid Fragments

Oligonucleotides, proteins, peptides, and carbohydrates are the best known biopolymers and one doesn’t have to explain how important each is to a number of biological functions.  The synthesis of these materials, or segments of them, are important in order to elucidate form and function.  Without access to various fragments of these molecules the study of them becomes difficult.  That’s one reason why genomics is ahead of proteomics which it ahead of glycomics, since oligonucleotides are easier to make that peptides which are easier to make than oligosaccharides.

In general, synthetic biopolymers are made either by solution phase chemistry of solid phase chemistry.  Solution phase chemistry has the advantage of better reactivity and the ability to monitor reactions and purify intermediates.  This means that you can use less amounts of monomer and reagents.  This also means, however, that syntheses can be quite labor intensive since purification is not always the easiest.  Solid phase methods, on the other hand, are highly labor efficient, but often times require large amounts of reagents and monomers due to the heterogeneous nature of the chemistry.  So the choice of solid phase or solution phase depends on a number of factors; accessibility to monomers, scale of synthesis, length of synthesis, etc.

Fluorous methods have been used in the synthesis of all three major classes of biopolymers.   Three major methods for the incorporation of fluorous techniques have emerged; fluorous capping, fluorous tagging, and fluorous supported synthesis.  The first two, capping and tagging, are used in conjunction with solid-phase methods.  The latter, fluorous supported synthesis, is a solution phase method where the solid phase is replaced by a fluorous tag.  The growing oligomer can then be purified each step along the way by either fluorous solid phase extraction (FSPE) or fluorous liquid-liquid extraction (FLLE).  Fluorous supported synthesis therefore tries to combine the main advantage of solution phase chemistry (lower stoichiometries) and the main advantage of solid phase chemistry (ease of purification).  This has been used to great effect in carbohydrate synthesis where just getting to the monomers can be difficult, so you don’t want to be using 5 equivalents of them.

A new ASAP paper in Organic Letters from researchers at Leiden University led by Codée and Van der Marel describe their use of fluorous supported synthesis in the preparation of fragments of teichoic acid, the best known of cell wall glycoproteins found in Gram-positive bacterial cell walls.  Not surprisingly these cell wall glycoproteins play an important, but not very well understood role in immunology and bacteriology.  Teichoic acid consists of repeating glycerol phosphate or ribitol phosphate units which are decorated with glycosyl and/or D-alanyl substituents.  Ready access to fragments of teichoic acid would allow further study of these interesting molecules to take place.  These same researchers have also reported traditional solution phase synthesis and solid phase synthesis of teichoic fragments and now extend that work to fluorous supported methods.

As the fluorous support they chose the F-Psc group as a phosphate protecting group.  The same authors developed the F-Psc group as a hydroxyl protecting group for carbohydrate synthesis a couple of years back and found it to be suitable as a phosphate protecting group.  They first then demonstrated it’s utility in techoic acid synthesis by producing glycerol phosphate oligomer shown below.  The synthesis was a 4 step cycle (phosphoramidite coupling, oxidation, DMT removal, and FSPE) that was repeated until the desired length was obtained after which the F-Psc group was removed by base and the secondary hydroxyls debenzylated by hydrogenation.  It proved to be quite successful and the FSPE was easily conducted for all of the compounds even as the oligomer grew longer.  Interestingly, the authors did note that as the oligomer grew longer that increasing amounts of phosphoramidite were required, so that once you got to an 18-mer you lost that advantage of solution phase chemistry.  Why that should be is unclear.

After demonstrating the value of the fluorous supported synthesis in the preparation of a unmodified teichoic acid, they then prepared a more complex version; a glycosylated hexamer 28 which also proved to be quite successful.  As a final demonstration the produced the fully glycosylated hexameric glycerol phosphate 39.  In each of these FSPE played a critical role as the last step of the 4 step coupling cycle.

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