ETD

• Nitroso Diels Alder

The main aim of this research project was to introduce modifications on our lead compound (M21) having the 1,3-diaza-4-oxabicyclic-[3.3.1]-nonene scaffold . This novel class of biologically active compounds acting as TRPA1 agonists and GLP-1 secretagogues was discovered in 2017 by Prof. Pineschi and colleagues through diversity-oriented synthesis (DOS). Our working hypothesis dealt with the introduction of an additional alkyne group on one of the two arene rings in order to perform a subsequent “click chemistry” approach on this functionality using a molecule containing an azide group present on a lanthanide probe synthesized by Prof. Di Pietro and co-workers thus establishing a covalent linkage between compound M-21 and the lanthanide probe.
This probe is composed of three main portions: the lanthanide center, represented in this case by europium; the macrocycle, which is 1,4,7-triazacyclononane; and the antenna portions, of which there are three—one for each nitrogen atom of the macrocycle. The antenna portion is able to bind sugars, enabling cell internalization, and they also act as chromophores capable of absorbing light and exciting the lanthanide center through energy-transfer phenomena, which leads to luminescence. Therefore, in principle, the probe could allow us to trace it by following the lanthanide luminescence and, consequently, to track compound M-21 derivative linked to it, enabling us to study its diffusion and compartmentalization.
As nitroso Diels–Alder reaction are currently performed using non–environmentally friendly oxidants, a photochemical-triggered alternative approach was preliminary investigated. Different solvents, photocatalysts, bases, additives, and various stoichiometric ratios between, 1,2-dihydropyridine, hydroxamic acid, photocatalyst etc were tested to identify the optimal reaction conditions, with the aim of improving the product yield while minimizing by-products and the collateral rearomatization of the 1,2-dihydropyiridine to pyridine.
A further aim of this thesis was to optimize the synthetic steps for M-21, specifically the final step, which is a cascade reduction using LiBHEt₃ as this reaction produced a considerable amount of a specific polar by-product.