Abstract
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).
Highlights
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 even biological properties
In order to make our own contribution en route to this goal, the stereoselective synthesis of a family of polyfluorinated hexopyranoses was accomplished using a Chiron approach
Structural analysis of the original 2,3,4,6tetradeoxy-2,3,4,6-tetrafluorohexopyranoside analog of galactose indicated that crystal packing overcompensates the 1,3-C−F bond repulsion
Summary
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 even biological properties. Numerous fluorinated carbohydrates were widely investigated as interesting and suitable imaging agents for 18F-positron-emitting tomography for cancer diagnosis,[25,26] in the footsteps of the early development of radiopharmaceutical [18F]FDG (2-deoxy-2-(18F)fluoro-D-glucose).[27] Fluorinated carbohydrates play interesting roles in biological systems as mechanistic probes or to modulate lectin−carbohydrate interactions.[28,29,30] Almost two decades ago, the group of DiMagno synthesized the hexafluorinated analog 331 (Fig. 1a) and this compound crosses red blood cell membrane at a tenfold higher rate than glucose This example indicates that increasing the polar hydrophobicity may be a useful strategy for improving biological molecular recognition.[32] This outcome has recently been proved accurate by the development of tetrafluoroethylene-containing monosaccharide 4 by the group of Linclau.[33,34] This compound gained affinity to UDP-galactopyranose mutase from Mycobacterium tuberculosis showing that tetrafluorination can have beneficial effect on binding compared to unmodified analogs
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