Synthesis of 1′-C-Fluoromethyladenosine

Abstract

In search for new antiviral agents, we have been interested in 1'-C-fluoromethyl branched ribonucleosides. In this paper, we describe the synthesis of 1'-C-fluoromethyladenosine via electrophilic fluorination of exo-glycal.

The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold

“…( Damont et al, 2007 ) These analogues utilized electrophilic fluorination of an exocyclic double bond at the C-1 carbon in order to install the fluoromethyl group at the 1′ position ( Damont et al, 2007 ). Unfortunately, like the 1′-methyl analogues, the 1′-fluoromethyl analogues also did not demonstrate any antiviral activity against bovine viral diarrhea virus (BVDV) or against hepatitis C virus (HCV) in a subgenomic replicon assay, however notably, the analogues were not toxic ( Damont et al, 2007 ). Due to the lack of any antiviral activity, they were not pursued further.…”

Nucleosides and emerging viruses: A new story

“…For instance, 1′-methyl- and 1′-fluoromethyl- led to compounds with little or no activity. [66] , [67] Other analogs were designed in which the N in the glycosidic bond was replaced by a carbon, leading to the development of 1′-substituted C -nucleosides. 68 These compounds are not substrates of N -glycoside hydrolases and phosphorylases, which cleave parent nucleosides.…”

1′-Cyano Intermediate Enables Rapid and Stereoretentive Access to 1′-Modified Remdesivir Nucleosides

“…Nucleoside analogue antivirals act, after bioactivation by host or viral kinases to active triphosphates, by competing with native nucleotides for incorporation by viral RdRp into nascent viral RNA, leading to either chain termination and prevention of viral replication or accumulation of lethal mutations in viral progeny. Since the approval of the first nucleoside analogue antiviralidoxuridine in 1962, the nucleoside analogue class has become the largest among antivirals in clinical use. , In pursuit of more anticancer and antiviral nucleoside analogues, extensive and productive modifications have since been made to the ribose and nucleobase moieties of the nucleoside scaffold, which an interested reader may learn more about in a recent two-part review by Seley-Radtke and Yates. , Extensions of the nucleoside approach seeking to bypass the rate-limiting initial phosphorylation of nucleosides by the installation of isosteric and isoelectric phosphonates (which also reduce susceptibility to cleavage by cellular phosphatases) at the 5′-OH position have proven an important development, and the bioavailability issues presented by such polar modifications are currently being tackled by phosphate esters, phosphonamidates, and phosphoramidates within the pro-nucleotide (ProTide) framework. − Modifications at the 1′ position, however, are fraught with issues of stability and early explorations at this position furnished analogues showing chemical instability or weak to no antiviral activity. − While the N-glycoside linkages of native nucleosides are generally physiologically stable, they are unstable to acid hydrolysis and the action of cellular hydrolases . Enzymatic cleavage of glycosidic bonds is generally catalyzed by nucleophile activation, nucleobase leaving group stabilization, and oxocarbenium ion stabilization .…”