The synthesis of polyfluorinated carbohydrates

Abstract

Carbohydrates are essential to many fundamental biological processes throughout Nature. Although generally specific for their cognate protein receptors, typical protein-carbohydrate affinities are only in the micromolar to millimolar range. Polyfluorination has emerged as an attractive strategy to enhance this affinity in order to develop carbohydrate-based inhibitors and therapeutics. This thesis describes three syntheses of 3,4-dideoxy-3,3,4,4-tetrafluoro-Dmannopyranose and D-glucopyranose.

Polyfluorination of carbohydrates has important consequences on the hydrogen bond properties of the adjacent alcohols and particularly, difluorination in the β-position of an alcohol group is expected to significantly reduce its hydrogen bond acceptor capacity. For these cases, the substitution of the alcohol group for the intrinsically more nucleophilic amino group is proposed in order to restore this hydrogen bond accepting capacity. Hence, the synthesis of 2-amino-2,3,4-trideoxy-3,3,4,4-tetrafluoro-D-mannopyranose, D-glucopyranose, 4-amino-2,3,4-trideoxy-2,2,3,3-tetrafluoro-D-galactopyranose and D-glucopyranose as well as 3-amino-2,3-dideoxy-2,2-difluoro-D-galactopyranose is reported in this thesis.

In the course of this work, a novel diastereoselective Honda-Reformatsky addition reaction of ethyl bromodifluoroacetate to various α-chiral α-oxygenated N-tert-butanesulfinylimines is described to access to α,α-difluoro-β-amino acids and 2,2-difluoro-3-amino carbohydrate analogues. In addition, an extension of the Konno procedure to introduce a tetrafluoroalkylidene moiety was developed.

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Identifiers

ORCID for Clement Fontenelle: orcid.org/0000-0002-1630-3407

ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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