The cell wall and/or capsule of many bacteria and other pathogenic microorganisms is covered by glycopolymers composed of oligosaccharide repeating units joined through anomeric phosphodiester linkages. Since these phosphoglycans are immunologically active components of numerous pathogens, the development of efficient routes for the chemical preparation of these biopolymers is a primary task.
A relevant example is the capsular polysaccharide (CPS) of Neisseria meningitidis X (Men X), a homopolymer of (1→4)-linked 2-acetamido-2-deoxy-a-D-glucosamine phosphate residues (Figure 1).
In 2006 WHO started to consider Men X as a substantial threat for public health, suggesting to include this serotype as antigenic component in anti meningococcal conjugate vaccines. Since vaccines currently available do not contain this component, we became interested in the synthesis of Men X CPS fragments. The chemical synthesis of glycosyl phosphosaccharides is however challenging, complicated by the difficult control of the correct stereochemistry at C-1 and the lability of anomeric phosphodiester linkages.
Among basic synthetic methodologies employed for the preparation of glycosyl phosphosaccharides, the phosphoramidite and the hydrogenphosphonate approaches are currently the most widespread techniques.1 The latter was recently used by us for the first synthesis of short chain Men X oligomers.2 This synthesis showed however some significant drawbacks, that prompted us to investigate new routes for more efficient preparation of even longer Men X fragments. In particular, we decided to explore the use of microfluidic reactors for the synthesis of glycosyl phosphosaccharides.
In this communication, we’ll describe our recent achievements in this field, showing that both glycosyl H-phosphonate and non anomerically linked H-phosphonate intermediates (Scheme 1) can be obtained in high purity under flow conditions, preserving the stereochemical integrity of the anomeric carbon.
Moreover, the first example of oxidative coupling (H-phosphonate approach) under microfluidic conditions will be described.
1 Carbohydr. Res. 2007, 342, 297-344
2 ARKIVOC 2013, 166-184
