Tackling challenges in asymmetric aminocatalysis for better sustainability

The concept of chirality is a recurrent fundament at the base of all animate and inanimate matter in the universe. We find chirality in everything around us, and that constitutes us. Reproducing reactions that introduce elements of asymmetry inside increasingly complex molecules is a concept that has been extensively explored in research in the past, present, and certainly will be in the future. The various synthetic strategies for carrying out an asymmetric synthesis of optically active compounds have, over the years, led to a change in these approaches towards the development of increasingly sustainable and green methodologies. The most outstanding contribution comes from pressure from global governments and the fact that it is ethically correct towards ourselves, our offspring, and our surroundings. According to the G20 report (Italy - August 2021), all member countries are committed to strengthening "the many synergies in financial flows for climate, biodiversity, and ecosystems" by alining the "investments towards sustainable development and growth" and "to build the necessary skills, innovations, and infrastructure". In this, asymmetric organocatalysis offered a good starting point. Since the catalysts used are often derived from natural sources, are non-toxic, stable to air and moisture, they do not need special requirements in the reaction set-up. During these three years of my PhD, I have tried to overcome, in my small way, those critical issues frequently found in the use of organocatalysis, and, in particular, focusing on aminocatalysis, always looking at the green aspect. To do this, I focused on a type of carbonyl compounds activation to perform catalysis via enamine mediated by the recurrent presence of an α-amino acid, Proline and its derivatives. The first project concerned the use of short heterochiral peptide sequences as catalysts to activate carbonyl compounds. In this work, we have demonstrated that it is possible to increase the catalytic efficiency of reactions carried out in aqueous media by exploiting a peptide sequence capable of pre-organising itself supramolecularly. The second work concerned the optimisation of a synthetic protocol using prolinol derivatives with alkyl chains in an aqueous solvent. In addition to optimising the synthesis of an important pharmacological precursor in a green solvent, the second strength of this work was the methodology used to find the optimal reaction condition, the DoE. The latest work reported is a study that attempts to clarify the phenomena that could hamper the success of a reaction mediated by a supported catalyst. Despite heterogenisation of catalyst for future recovery and reuse being an extremely attractive concept for industry, there are still some critical issues related to the imperfect inertia of the support itself. With this aim, we have studied the relationship between activity and affinity for the matrix of substituted series of benzaldehydes that could lead to substrate inhibition in an aldol reaction with hydroxyacetone.