Sustainable Synthetic Methodologies for New Antiviral Production

This thesis investigates novel synthetic methods to access antiviral compounds, focusing on three key areas: the development of modified nucleosides, the exploration nucleotide chemistry to access a novel NAADP derivative and the optimization of the industrial scale process for producing an active pharmaceutical ingredient (API). Nucleosides, as essential building blocks of DNA and RNA, are involved in many cellular processes. Their modified counterparts, known as nucleoside analogs, mimic natural nucleosides and are able to interfere with cellular processes, becoming critical in treating various disease including viral infections and cancer. Due to its favourable properties, morpholine was used as a ribose surrogate for the synthesis of a class of modified nucleosides which are called “morpholino nucleosides”. The first objective of this thesis consisted in developing an alternative synthetic route for morpholino nucleosides, a promising class of nucleoside analogs. Using enantiopure glycidol as starting material, a novel pathway was devised to produce optically pure morpholino nucleosides. Central to our strategy is a functionalization step of the key intermediate, morpholine hemiacetal, with natural or modified nucleobases under Lewis acid-promoted glycosylation conditions. Optimization studies led to the identification of TMSOTf as the most effective Lewis acids, which predominantly yielded β-anomers. This study presented an adaptable strategy for morpholino nucleoside synthesis, opening avenues for further investigation into their biological potential. Research carried out during the six months at the University of Hamburg contributed to a deeper understanding of nucleoside chemistry, focusing on synthesizing a membrane-permeable derivative of nicotinic acid adenine dinucleotide phosphate (NAADP), a key molecule involved in calcium-mediated signaling. The work involved the development of a new method for the independent access, through different strategies, to modified adenosine and stabilized nicotinic acid derivatives. These advances enhance the understanding of nucleotide modifications and their applications in medicinal chemistry, particularly in signal transduction. Collaboration with OLON S.p.A. was dedicated to the optimization of the large-scale synthesis of an API focusing on three main objectives. To improve efficiency and sustainability, an enantiopure piperidine derivative was used as substrate instead of the racemic mixture, increasing reaction specificity and bypassing the resolution step. Refinements in the challenging nucleophilic aromatic substitution step simplified the processes, reducing waste while enhancing scalability. A combined deprotection and acylation method was developed, achieving the same high yields and purity while minimizing complexity. These innovations align with green chemistry principles, reducing environmental impact and supporting industrial-scale pharmaceutical production.