Alternative methods and cross-coupling reactions, Heck-Cassar-Sonogashira/Suzuki/Catellani, for the synthesis of bioactive molecules and the development of sustainable approaches for new peptide synthesis

The first part is dedicated to palladium-catalysed cross-coupling reactions. We have investigated the copper free Heck-Cassar-Sonogashira (HCS) reaction mechanism. In fact, despite its wide application and huge success, the mechanism was still under discussion. Experimental results and theoretical calculations were helpful in shedding light on the preferred pathway. In addition, a complete guide to the efficient in situ activation of the L2PdX2 pre-catalyst was presented, as this was not yet available. Pd(OAc)2 and Pd(ACN)2Cl2 were chosen as pre-catalysts and the reduction process was monitored by 31P NMR in the presence of different ligands, solvents and temperatures. Finally, a sustainable approach was described for Heck-Cassar and Suzuki-Miyaura reactions in the presence of aryl chlorides, which are the less expensive and available aryl halides. The strategy developed was also applied to the synthesis of two fungicides such as Boscalid and Fluxapyroxad. The second part describes the development of green methodologies for peptide synthesis and the design of potential new antimicrobial peptides for intestinal diseases. We have investigated cyclic propylphosphonic anhydride (T3P®) and demonstrated its ability to replace the classical and hazardous coupling reagents in LPPS and SolPPS. In addition, these new protocols have been applied to the synthesis of potential new antimicrobial peptides (AMPs). The third part of the research was carried out at the University of Oxford under the supervision of Professor Véronique Gouverneur.Fluorinated compounds are widely used in the agrochemical and pharmaceutical sectors as the incorporation of fluorine modifies the physicochemical and biological properties of bioactive molecules. In particular, I focused on the development of catalytic enantioselective fluorination strategies of neutral electrophiles with KF, allowing the avoidance of expensive reagents.