Access to inter-nucleoside C-C links by metal-catalyzed cross-coupling reactions on glycal-type nucleosides – CatACLiSM

The importance of oligonucleotides (ON) pushed chemists to develop powerful syntheses to build them. Currently, the access to natural ON has become an efficient automated process. Nevertheless, the natural link is rapidly hydrolyzed in physiological media. Unnatural ON were thus explored to reach more stability, specificity, etc. and lower toxicity. Particularly, unnatural ON having mimic C-C links are of primary interest due to their stability and their similarity compared to natural ON. However, the elaboration of a C-C link between two nucleosides remains challenging. The goal of this project is to offer an innovative alternative to build unnatural bonds in position 3’ of nucleosides from easily accessible structures and to extend the structural scope of nucleosides. The strategy is based on the use of metal-catalyzed cross-coupling reactions (MCC) on glycal-type nucleosides (NuG), very scarce in the literature. For the past few years, we have been acquiring expertise in the synthesis of C-glycoanalogues via MCC. This project tends to capitalize on our expertise and the expertise of Prof. Lecouvey in the synthesis of complex phosphorus-containing molecules. The first objective will be the set-up of the MCC methodology. The second objective will consist in applying this reactivity to the synthesis of small oligomers. The third objective will aim to extend this reactivity to various complex phosphorylated reagents. The project will involve a PhD in co-supervision, a post-doctoral position and two Master 2 internships. The proposal will also include missions for the consortium and will pay the global working.