Synthesis of 2,3-Dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses and Their Use in the Preparation of Conformationally Locked Bicyclic Nucleosides

Abstract

Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons-Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2',3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-2',3'-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an (o)E/(o)T1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.

Synthesis of Monofluoroalkenes: A Leap Forward

“…The fluoroolefination of ketones with α-fluorophosphonates is a good way to install a tetrasubstituted monofluoro-alkene with good selectivity towards the E isomer. Examples of this strategy are its utilization in the preparation of conformationally locked fluorinated bicyclic nucleosides 202 as well as fluoroalkene-based pseudopeptides. 6c, 203 With the goal of synthesizing both the E and Z isomers of rac-N-Cbz-Gly-Ψ[CF=C]-Pro-OH, Sano and co-workers optimized the olefination of 2-substituted cyclopentanones.…”

Control of α/β Anomer Formation by a 2′,5′ Bridge: Toward Nucleoside Derivatives Locked in the South Conformation

“…In this work, we studied synthetic approaches toward yet unprecedented 2′,5′-bridged ribonucleoside analogues. Our original target was inhibition of HCV RNA-dependent RNA polymerase (RdRp) which seems to tolerate both North and South ribose conformations , as well as substituents at positions 2′ and 5′ once the nucleosides derivatives are converted into their corresponding appropriate monophosphate prodrugs. , Indeed some of the 2′ substituents in proximity to the nucleobase itself can be quite large including alkynyl , and retain potent activity toward viral polymerases, suggesting that some steric bulk on the endo face is tolerated. We were also interested in exploring the structure–activity relationships of the 2′,5′-locked conformation strategy on the endo face toward purine receptors and other related targets.…”