Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism

Abstract

Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2′,3′-dideoxy-2′,3′-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2′,3′-dideoxy-2′,3′-difluoro and a 2′-deoxy-2′-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.

2’‐Derivatisation of 3’‐C‐Methyl Pyrimidine Nucleosides

“…Unfortunately, the retention of the configuration of C‐2’ sugar residue demonstrates that this strategy cannot circumvent the neighboring group participation by the respective O 2 ‐atom in fluorination conditions. Using N 3 ‐benzyl uridine analogs, similar results have just been reported during the writing of this article [30] …”

“…Using N 3 -benzyl uridine analogs, similar results have just been reported during the writing of this article. [30] Azidation. The N 3 -protected nucleoside 15 treated under the conditions used for the preparation of nucleoside 11 (Scheme 3) gave rise to a complex mixture of at least three compounds (see supporting information).…”

Multi-Enzymatic Cascades in the Synthesis of Modified Nucleosides: Comparison of the Thermophilic and Mesophilic Pathways

“…Immobilized thermophilic nucleoside phosphorylases have been used in the polyenzymatic synthesis of several halogenated nucleoside analogs: cladribine [ 4 ], 2-fluoro-2′-deoxyadenosine, and fludarabine [ 16 ]. The synthesis of halogenated nucleosides is of particular interest, since they exhibit a broad spectrum of biological activity [ 9 , 17 ].…”

The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

“…369 Finally the Goss group reported a direct DAST-mediated deoxyfluorination with 5-protected uridine (Scheme 101). 379 The substrate 709 was synthesized via acetonide protection of the ring alcohols, benzylation at OH-5, and acetonide hydrolysis. Reaction of DAST with the diol led to the formation of (protected) 1-(2′,3′-dideoxy-2′,3′-difluoro-β-D-xylofuranosyl) uracil 714 in 11% yield, alongside the corresponding C-2monofluorinated derivative 716 in 53% yield.…”