Stereoselective glycal fluorophosphorylation: synthesis of ADP-2-fluoroheptose, an inhibitor of the LPS biosynthesis.
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.
Dohi
Hirofumi
H
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).
Périon
Régis
R
Durka
Maxime
M
Bosco
Michael
M
Roué
Yvain
Y
Moreau
François
F
Grizot
Sylvestre
S
Ducruix
Arnaud
A
Escaich
Sonia
S
Vincent
Stéphane P
SP
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
D017611:Fluorine Compounds; D008070:Lipopolysaccharides; D011134:Polysaccharides; D011506:Proteins; D000244:Adenosine Diphosphate