Selectfluor and NFSI exo‐Glycal Fluorination Strategies Applied to the Enhancement of the Binding Affinity of Galactofuranosyltransferase GlfT2 Inhibitors

Abstract

Two complementary methods for the synthesis of fluorinated exo-glycals have been developed, for which previously no general reaction had been available. First, a Selectfluor-mediated fluorination was optimized after detailed analysis of all the reaction parameters. A dramatic effect of molecular sieves on the course of the reaction was observed. The reaction was generalized with a set of biologically relevant furanosides and pyranosides. A second direct approach involving carbanionic chemistry and the use of N-fluorobenzenesulfonimide (NFSI) was performed and this method gave better diastereoselectivities. Assignment of the Z/E configuration of all the fluorinated exo-glycals was achieved based on the results of HOESY experiments. Furthermore, fluorinated exo-glycal analogues of UDP-galactofuranose were prepared and assayed against GlfT2, which is a key enzyme involved in the cell-wall biosynthesis of major pathogens. The fluorinated exo-glycals proved to be potent inhibitors as compared with a series of C-glycosidic analogues of UDP-Galf, thus demonstrating the double beneficial effect of the exocyclic enol ether functionality and the fluorine atom.

Synthesis of Unprecedented Sulfonylated Phosphono‐exo‐Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes

“…The H-2 chemical shifts were recorded at 6.3-5.4 ppm for the (Z) isomersa nd 5.5-4.9 ppm for the (E)i somers. As imilar trend was observed for the 31 P-signal chemical shifts, which were recorded between 19.7-17.8 ppm for the (Z)i somers and be-tween 17.7-16.4 ppm for the (E)i somers.I na ddition, the coupling constants between C-1 and the phosphorous atom were always between 38-42 Hz when these two elements are trans, while this coupling constantw as always close to 10 Hz when the 13 Ca nd the 31 Pa re cis ( Table 2).…”

“…The Z/E assignment of tetrasubstituted exo-glycals is challenging, because the exocyclic doubleb ond of 29-36 is substituted by four distincte lements (O, C, S, andP ). However,t heir structures have been fully ascertained by NMR spectroscopy, using 1 H, 13 C, 31 P, 1 H/ 1 Hc orrelations, and 1 H/ 13 Cc orrelations (HSQC, HMBC). To demonstrate the configurations of all exoglycals reported in this study,1 Dh omonuclear NOE spectra (1D NOE) were also acquired and compared for each E/Z diastereomericpair.…”

“…[6] The first transferase (GlfT1) [7] adds the two initial galactofuranose( Galf)u nits to the disaccharide linker, while the second transferase (GlfT2) [3a, 8] catalyzes ap olymerization [9] that yields af inal galactan composed of 30-35 galactofuranose moieties ( Figure 1A). [13] The principle used in the design of these compoundsi st hat the sp 2 hybridization of the anomeric carbon of the phosphonylated exo-glycals 3, 4,or6 may lock the molecule in aconfor-mation mimickingt he putative oxacarbenium-ion-like transition state 5 ( Figure 1C). Several attempts have been made to inhibit UGM, [2a, 11] but only very few inhibition studies of GlfT1 and GlfT2 have been described so far.…”

“…[2a, 12] In previous studies, we discovered that exo-glycals such as 3 and 4-(Z,E) could inhibit UGM and/or GlfT2 ( Figure 1B). [13] The principle used in the design of these compoundsi st hat the sp 2 hybridization of the anomeric carbon of the phosphonylated exo-glycals 3, 4,or6 may lock the molecule in aconfor-mation mimickingt he putative oxacarbenium-ion-like transition state 5 ( Figure 1C).…”

Copper Salt‐Controlled Divergent Reactivity of [Cu]CF2PO(OEt)2 with α‐Diazocarbonyl Derivatives

“…α‐Fluorovinylphosphonates were already recognized as phosphate mimics . Usual accesses to this class of compounds relied on an olefination reaction,– a cross‐coupling reaction, the fluorination of vinylphosphates or after a fluoride elimination,– usually with moderate stereocontrol. In contrast, thiodifluoromethyl phosphonate derivatives remain underexplored despite the potential of this emerging fluorinated group, and the access to this motif is poorly documented so far…”