The replacement of hydroxyl groups by fluorine atoms on hexopyranose scaffolds may allow access to the discovery of new chemical entities possessing unique physical, chemical and ultimately even biological properties. The prospect of significant effects generated by such multiple and controlled substitutions encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated hexopyranoses, six of which are unprecedented. Hence, we report the synthesis of heavily fluorinated galactose, glucose, mannose, talose, allose, fucose, and galacturonic acid methyl ester using a Chiron approach from inexpensive levoglucosan. Structural analysis of single-crystal X-ray diffractions and NMR studies confirm the conservation of favored 4C1 conformation for fluorinated carbohydrate analogs, while a slightly distorted conformation due to repulsive 1,3-diaxial F···F interaction is observed for the trifluorinated talose derivative. Finally, the relative stereochemistry of multi-vicinal fluorine atoms has a strong effect on the lipophilicities (logP).

In this work, we have developed synthetic routes for novel trifluorinated glucopyranose analogues using a Chiron approach. This strategy used inexpensive levoglucosan as a starting material, and we achieved a microwave glycosylation method as a key step. All analogues adopted standard 4 C 1 glucopyranose conformations, and a gauche−gauche conformation for the fluoromethyl group (C5−C6 linkage) was ascertained for congeners with a fluorine atom at C-6. Finally, the lipophilicity of trifluorinated glucose analogues was assessed with a log P determination method based on 19 F NMR spectroscopy.

In this work,w es ynthesized all mono-, di-, and trifluorinated glucopyranose analogues at positions C-2, C-3, C-4, and C-6. This systematic investigation allowed us to perform direct comparison of 19 Fr esonances of fluorinated glucose analoguesa nd also to determine their lipophilicities. Compounds with af luorine atom at C-6 are usually the most hydrophilic, whereas those with vicinal polyfluorinated motifs are the most lipophilic. Finally, the solvation energies of fluorinated glucosea naloguesw ere assessed for the first time by using density functional theory.T hism ethoda llowedt he log P prediction of fluoroglucose analogues, whichw as comparable to the Clog P valueso btained from various web-basedp rograms.

There is a growing interest in the preparation of polyfluorinated carbohydrates. A limited number of fluorohexopyranosides have been used in biological investigations because of the synthetic challenge they present. Hence, we report the synthesis of fluorinated homodimer, fluorodisaccharides, C‐terminal fluoroglycopeptides, lipoic acid fluoroglycoconjugate and trifluoroallopyranoside derivatives functionalized at C‐6. Our strategy uses levoglucosan as inexpensive starting material and facilitates an approach to complex carbohydrate analogues with multiple C−F bonds. The challenge of our synthetic route centered around an efficient preparation of crucial 1,6‐anhydro‐2,4‐dideoxy‐difluoroglucopyranose and focused on achieving a difficult glycosylation of the trifluoroallopyranose donor. The results clearly highlight challenges related to the preparation of polyhalogenated complex organic molecules and pave the way to access novel medically relevant tools.