Application de la stratégie de séparation de phase à la synthèse de macrocycles complexes et développement d’une réaction de thioalcynylation pour la synthèse de macrocycles sulfurés
Macrocyclization reactions can be problematic due to poor selectivity of cyclization versus oligomerization. As such, difficult purification of complex mixtures and/or the use of complex and cumbersome experimental setups are often necessary. The drawbacks can complicate synthetic pathways and deter chemists from exploring the unique chemical space of macrocycles. Our group has developed a new macrocyclization strategy called phase separation strategy, a protocol enabling one-pot macrocyclization reactions at much higher concentration. In the present thesis, the challenges associated with macrocyclization reactions are tackled by the development and the application of new strategies. First, the phase separation strategy protocol was used to synthesize the backbone of complex macrocycles like the natural product ivorenolide A (Chapter 4) and the antiviral vaniprevir (Chapter 6). With the use of the phase separation strategy protocol, macrocyclization reactions were performed at concentrations 120 times higher than traditional protocols while maintaining a high level of macrocyclization selectivity. Second, the development of a new copper-catalyzed synthesis of alkynyl sulfides for the synthesis of a macrocyclic peptide library is described (Chapter 8). The macrocyclic peptides were also tagged with several biomarkers by diversification of the resulting alkynyl sulfide motif. Finally, the scope of the intermolecular copper-catalyzed reaction was explored (Chapter 9). Using the method, bis-heteroatom substituted alkynes were synthesized and modification of unprotected cysteine sidechains was possible. Furthermore, the mechanistic reaction pathway of the new alkynyl sulfide synthesis was studied experimentally and computationally.
Macrocycle Ivorenolide A Macrocyclization Macrocycle Phase separation Alkynyl sulfide Copper