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Selectfluor and NFSI exo ‐Glycal Fluorination Strategies Applied to the Enhancement of the Binding Affinity of Galactofuranosyltransferase Gl f T2 Inhibitors
Author(s) -
Dumitrescu Lidia,
Eppe Guillaume,
Tikad Abdellatif,
Pan Weidong,
Bkassiny Sandy El,
Gurcha Sudagar S.,
Ardá Ana,
JiménezBarbero Jesús,
Besra Gurdyal S.,
Vincent Stéphane P.
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201404180
Subject(s) - selectfluor , chemistry , glycal , fluorine , glycosidic bond , stereochemistry , combinatorial chemistry , organic chemistry , enzyme , stereoselectivity , catalysis
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 Gl f T2, 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‐Gal f , thus demonstrating the double beneficial effect of the exocyclic enol ether functionality and the fluorine atom.