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

Abstract

ABSTRACT 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.