Stereoselective Glycal Fluorophosphorylation: Synthesis of ADP-2-fluoroheptose, an Inhibitor of the LPS Biosynthesis

Heptosides are found in important bacterial glycolipids such as lipopolysaccliaride (LPS). the biosynthesis of which is targeted for the develoopment of novel antibacterial agents. This work describes the synthesis of a fluorinated analogue of ADP-L-glycero-beta-D-manno-heptopyranose, the donor substrate of the heptosyl transferase WaaC, which catalyzes the incorporation of this carbohydrate into LPS. Synthetically, the key step for the preparation of ADP-2F-heptose is the Simultaneous and stercoselective installation of both the fluorine atom at C-2 and the phosphoryl group at C-1 through a selectfluor-mediated (selectfluor= 1-clilol-omettivi-4-fluorodiazonia-bicy[2.2.2]octane bis(triflate)) electrophific addition/nucleophilic substitution involving a heptosylplycal. Therefore, we detail in this article 1) the stereoselective preparation of the key intermediates heptosylglycals, 2) the development of a new fluorophosphorylation procedure allowing an excellent beta-gluco stereoselectivity with all-equatorial glycals, 3) the synthesis of the target ADP-2F-heptose, and 4) some comments on the contacts observed between the fluorine atom of the final molecule and the protein in the crystallographic structure of heptosyltransferase WaaC.