• nitroso Diels-Alder
• 3.3-sigmatropic rearrangement
• bicycles
• asymmetric synthesis
• obesity
• diabetes
• glp-1
• trpa1

The number of people diagnosed every year with type 2 diabetes mellitus and obesity is growing quite rapidly - especially in countries with a high standard of living - and it has been steadily increasing in the last decades. These diseases are going to be an ever-growing burden on healthcare systems worldwide and this issue needs to be addressed with new and more effective pharmacological treatments. In the last years, there has been a lot of interest in investigating GLP-1, a peptide hormone involved in glucose homeostasis, and its metabolic pathway to find potential targets for novel and innovative drugs, but only a few orally available and easily accessible medications have been approved for human use.
In 2017, in Prof. Pineschi’s laboratory, a novel molecular scaffold (1,3-diaza-4-oxa-[3.3.1]non-6-ene) was synthesized and it was later found to be a secretagogue of GLP-1 both in vitro and in vivo, making it a possible drug candidate for the treatment of diabetes mellitus and obesity.
Since then, a library of compounds derived from the same active scaffold was synthesized, in order to carry out a structure-activity relationship study, following a well-established four-step general synthesis:
1. Synthesis of N-acyl-1,2-dihydropyridines from pyridine
2. Nitroso Diels-Alder reaction between the N-acyl-1,2-dihydropyridines and an in situ generated acyl nitroso derivative
3. Hetero-Cope rearrangement of the inverse Diels-Alder cycloadducts
4. Reduction with LiEt3BH
The active molecules contain three stereogenic centres, but the general synthesis allows us to obtain them only as a racemic mixture. The scope of this thesis is to synthesize optically active final compounds in both enantiomeric configurations, in order to evaluate if there is a significant difference in biological activity between the two stereoisomers, allowing us to understand which one is the eutomer, if present. The asymmetry is introduced in the synthesis of the N-acyl-1,2-dihydropyridine, which is afforded as a single enantiomer by a multi-step synthetic pathway. It is then reacted with an acyl nitroso derivative, introducing the other two chiral centres, which, since the nitroso Diels-Alder is a stereoselective reaction, are determined by the stereochemistry of the N-acyl-1,2-dihydropyridine. Finally, the last two steps of the general synthesis afford the optically active final compound with a defined and known stereochemistry.