Synthèse stéréosélective de centres tertiaires et quaternaires par voie radicalaire et leur application à la synthèse d’analogues de nucléosides et de polypropionate

One of the interests of our laboratory is the synthesis of tertiary and quaternary stereogenic centers using diastereoselective radical transfers on acyclic substrates. Another interest is the biological applications of molecules possessing tertiary and quaternary centers. The first part of this thesis aims to discover new antiproliferative agents within the family of nucleoside analogues. Currently used chemotherapy drugs, for example Gemcitabine, AraC or 5-FU, suffer from many limitations, such as poor bioavailability and toxicity. The objective of this thesis is to develop new drugs that address the limitations that plague the standard treatments for pancreatic cancer. The molecules we conceptualized bear an all-carbon quaternary center that may give them specific biological properties. An efficient synthetic route on a multi gram scale (e.g., 15 steps, 29% overall yield) using the radical chemistry developed in our laboratory made it possible to synthesize different nucleoside analogues. In a SAR study, a library of more than 60 nucleoside analogues was synthesized by incorporating different nucleobases, phosphoramidates in the C3’ and / or C5’ position and lipoates. The in vitro and in vivo efficacy of these new nucleoside analogues was examinated in Pr. Mona Nemer's laboratory at the University of Ottawa. The novel analogues were tested against different cell lines derived from solid tumors. Among them, several compounds showed μM IC50 values, as well as over 90% inhibition of cell proliferation. In order to discover the mechanism of action of this new family of nucleoside analogues, photoaffinity probes were synthesized. iv The second part of this thesis focuses on the synthesis of polypropionate using a radical based approach. A very effective method was previously developed by our laboratory to obtain all polypropionate configurations in high selectivity by varying the choice of Lewis acid at the key Mukaiyama aldolisation and hydride transfer steps. Despite recent advances in diastereoselective and enantioselective free radical-based processes, their usefulness and practicability continue to be plagued by the necessity of tin reagents, such as Bu3SnH, to achieve an effective hydrogen transfer. The aim of the second part of this thesis was to remove tin from the synthesis of polypropionates while maintaining high yields and selectivities. No precedent exists for the creation of stereogenic centers using a radical based approach with NHC-boranes. Due to our interest in the synthesis of polypropionate and the desire to form these motifs in the absence of tin, we investigated if NHC-boranes could be used as effective hydrogen transfer reagents at low reaction temperatures in the presence of a Lewis acid. It was demonstrated that the use of mild Lewis acids can expand the scope of NHC-boranes in hydrogen transfer radical reductions providing excellent 2,3-syn selectivity. A diastereoselective radical-based reduction, leading to the 2,3-anti isomer, can be achieved by combining the efficacy of NHC-boranes as a chain propagator with that of thiol derivatives. A new synthetic method for stereoselective radical reductions without the use of tin hydride has thus been developed.

Keyphrases: Cancer, NHC-borane, Mukaiyama aldol, Nucleoside, Pancreas, Photoaffinity labeling, Prodrug strategy, Quaternary center, Radical reduction