3-Deoxy-3-Fluoro Mannuronic Acid Alginates: Stereoselective Automated Synthesis and Conformational Behaviour

Fluorination is a powerful strategy for the editing of glycans, creating bespoke tools to probe carbohydrate-protein recognition and processing. Positioning the site for fluorination within a glycan is critical, whether examining bonding interactions or installing benign reporter capability. Herein, we study the effect of C-3 fluorination of mannuronic acids in the assembly of β-1,4-d-mannuronic acid alginate fragments and the effect of these point mutations on the conformational preference of the generated oligosaccharides. We explore the synthesis and glycosylating properties of a 3-deoxy-3-fluoro d-mannuronate donor to establish that the C-3 fluoride does not thwart the high β-stereoselectivity of the mannuronate system. Subsequent deployment of these building blocks in automated glycan assembly enables the preparation of a small library of β-d-mannuronate oligosaccharides containing the C-3-F modification. Comprehensive NMR analysis shows that even though the 3-deoxy-3-fluoro units disrupt the native inter-residue C3-OH•••O5 hydrogen bonds, the overall conformation remains in line with that of the native β-1,4 mannuronic acid alginate. This indicates tolerance for this modification in these structural tools and provides an exciting foundation to study self-assembly and enzymatic processing of β-1,4 mannuronic acid oligosaccharides.