Stereoselective Process involving radicals. Synthesis and Methodology.

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One of the long-term objectives of our research program is to contribute from a strategic and theoretical standpoint with approaches leading to the creation of new stereogenic centers on acyclic molecules. Of particular interest to us is the development of approaches involving free radical intermediates. These studies have already led to the development of various tools, which we plan to use in the synthesis of natural products of biological interest or analogues thereof, as part of our medicinal chemistry efforts.***Stereoselective free radicals reactions and synthesis of biologically relevant molecules. We have studied diastereoselective hydrogen transfer and allylation reactions on carbon-centered radical flanked by an ester and a stereogenic center. The scope of these reactions and their mechanisms has been studied thoroughly experimentally and by DFT calculations. We plan to further develop these methodologies by exploring diastereoselective fluorination and other radical addition reactions. Combining the hydrogen transfer with the Mukaiyama aldol reaction led us to develop one of the most general approach to the synthesis of polyketides (Zincophorin, Ionomycin, etc.). One of the emerging molecule of interest to eradicate cancerous stem cells (CSC) resistant to existing drugs, is Salinomycin, a member of the polyketide family. We plan to identify the portions of the molecule responsible for its activity (i.e. pharmacophores) and synthesize simplified analogues.***Synthesis of nucleoside analogues. In the last granting period, we have demonstrated that we can synthesize sterically encumbered nucleosides that were prepared with great difficulty in the past. Using the free radical reactions developed by our group, we recently succeeded in preparing acyclic molecules having an all-carbon stereogenic quaternary center, flanked by various functionalities. These molecules can be used to prepare acyclic and cyclic nucleoside analogues by taking advantage of the reaction sequences previously studied in our laboratory. Using these approaches, and others proposed herein, we will prepare two novel families of nucleoside analogues bearing a quaternary center at C3' or C2' that present an important medicinal potential.***Synthesis of a mimic of a bioactive polysaccharide. We have recently hypothesized and reported that a small molecule with a conformational bias could replace advantageously one of the subunit of a bioactive polysaccharide. In our first study, we chose to modify sialyl Lewis X (sLex) as a proof of principle. We plan to expand our study by testing other acyclic small molecules in this context.**