The Shortest Strategy for Generating Phosphonate Prodrugs by Olefin Cross‐Metathesis – Application to Acyclonucleoside Phosphonates

Abstract

A short synthetic route to phosphonate prodrugs by olefin cross-metathesis, which uses either (acyloxymethyl) or (hexadecyloxypropyl) allylphosphonate building blocks is described. A study of eight ruthenium catalysts including the Ru-indenylidene catalyst, which bears the N-heterocyclic

Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates

“…Thanks to this breakthrough approach, some (E)-but-2-enyl C5substituted thymidine phosphonoamidates 19e22 were obtained in yields ranging from 38% to 44%, (Scheme 4). Based on our previous data [22], the 5-fluoro-(23) and 5-chloro-(24) analogs, which are bioisosteres of methyl group, were obtained, in 35% and 36% yield, respectively.…”

“…The introduction of these biolabile prodrugs revealed the potential of our ANPs to inhibit HCMV replication (EC 50 's in the range of 13e70 mM for compounds 19,20,21,22), hitherto undetected under other pronucleotide forms. Several hypotheses can support these results, as a better bioavailability of these molecules under the phosphonoamidate form compared to the other prodrug forms.…”

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…42 Bis(POM)- and bis(POC)-allylphosphonates were generated by reaction of dimethyl allylphosphonate with either POM-Cl and POC-Cl in the presence of sodium iodide (Scheme 19). Interestingly, the authors showed that very low conversion rates were observed when diethylallyl phosphonate was used instead of dimethyl allylphosphonate.…”

Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides

“…We turned then our attention to the synthesis of the pyrazinecarboxamide derivative 14 since, among the modified nucleobases, a series of pyrazinecarboxamide derivatives (including T-705, favipiravir) developed by Furuta et al [17,18] have demonstrated good activity in various RNA viral infections. In a first attempt, we struggled to introduce the pyrazine moiety through direct N-alkylation of 10 with the corresponding (E)-4-phosphonobut-2 0 -en-1 0 -yl bromide (9), in the presence of K 2 CO 3 in anhydrous DMF, (Pathway A). Unfortunately only the bis(POM)-but-1,3-dienyl phosphonate 9 0 resulting from undesired bromine elimination was obtained, (Scheme 3).…”