title: Stereoselective glycal fluorophosphorylation: synthesis of ADP-2-fluoroheptose, an inhibitor of the LPS biosynthesis.
abstract: Heptosides are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development 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 stereoselective installation of both the fluorine atom at C-2 and the phosphoryl group at C-1 through a selectfluor-mediated (selectfluor=1-chloromethyl-4-fluorodiazoniabicyclo[2.2.2]octane bis(triflate)) electrophilic addition/nucleophilic substitution involving a heptosylglycal. 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.
authors.affiliation: Ecole Normale Supérieure, Département de Chimie, Institut de Chimie Moléculaire (FR 2769), UMR 8642: CNRS-ENS-UPMC Paris 6, 24 rue Lhomond, 75231 Paris Cedex 05 (France).
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Dohi
authors.forename: Régis
authors.initials: R
authors.lastname: Périon
authors.forename: Maxime
authors.initials: M
authors.lastname: Durka
authors.forename: Michael
authors.initials: M
authors.lastname: Bosco
authors.forename: Yvain
authors.initials: Y
authors.lastname: Roué
authors.forename: François
authors.initials: F
authors.lastname: Moreau
authors.forename: Sylvestre
authors.initials: S
authors.lastname: Grizot
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ducruix
authors.forename: Sonia
authors.initials: S
authors.lastname: Escaich
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry*; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008070:Lipopolysaccharides / Q000096:biosynthesis* / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D011134:Polysaccharides / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D017611:Fluorine Compounds; D008070:Lipopolysaccharides; D011134:Polysaccharides; D011506:Proteins; D000244:Adenosine Diphosphate