Synthesis and reactivity of aryl iodo difluorides

Organofluorine substrates are molecules of increasing demand in both academic and industrial settings. Organofluorine compounds are very rare in nature and therefore several approaches to their synthesis have been developed. In the work performed during this research tenure, the approach towards the synthesis of organofluorine substrates is based on the use of hypervalent iodine reagents. The structure of the research program can be summarized into three main sections: Synthesis of aryl iodo difluorides; Reactivity of aryl iodo difluorides towards organoselenium substrates; Approach toward stereoselective fluorinations with the synthesis of chiral iodo difluorides. Aryl iodo difluorides reagents have been known for more than a century but they have not been extensively used mainly due to their difficulty of synthesis, which require harmful and hazardous reagents. We have developed an alternative method for their preparation involving three synthetic steps: perborate oxidation of an aryl iodide, followed by basic hydrolysis and subsequent treatment with hydrofluoric acid. A number of aryl iodo difluorides were synthesized using this procedure and each of them is characterized by high purity and high yield. The reactivity of (difluoroiodo)toluene (DFIT) as a fluorinating agent was tested on organoselenium substrates. a-Seleno esters, amide and nitriles undergo a-fluorination when treated with 2 equivalents of DFIT. Under these conditions, the monofluoro derivatives were obtained with yields ranging from 20% to 65%. Additionally, (difluoroiodo)toluene can be employed in oxidative fluorinations. The exploitation of its oxidative nature produced tetraethyl ammonium iodo difluoride, and preliminary results indicate that it can be used as fluorinating agent, as well. The third aspect of the research dealt with stereoselective fluorination reactions. The synthesis of an opportune chiral iodo difluoride can provide the further development of hypervalent iodine reagents as fluorinating reagents. Different substrates were used to reach this goal and the study conducted in this direction brought about the synthesis of a difluoride with the iodine atom in oxidation state V, which can be use as chiral fluorine transfer after a simple modification of its structure

Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2′-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases