The project aims at investigating new frontiers in the field of organocatalysis, and it targets the design and realization of catalytic batch and flow systems for enantioselective organocatalytic synthesis, using immobilized catalysts and co-catalysts. Covalently immobilized, smart organocatalysts will be realized, fully characterized and employed in challenging enantioselective reactions. Heterogeneous systems combine in a useful enabling platform leading to valuable chiral, small organic molecules (drugs, agrochemicals) in highly enriched enantiomeric forms, and their use under flow mode conditions is considered a promising green procedures with potential for intensification. The project is focused around the following "tools": 1) mesoporous silica, monolithic polymers with dual micro- and meso-porosity, all with tunable surface chemistry and amenable for chemical functionalization; 2) chiral organonocatalysts based on chinconan alkaloids and acidic co-catalysts; 3) electrospray ionization mass spectrometry ESI-MS for screening the reactivity of catalysts, monitoring organic and organometallic reactions by detection of reactants, intermediates and products and eventually elucidation of reaction mechanism. Innovative immobilization strategies of privileged chiral organocatalysts (cinchonan derivatives, 1,2-diamines) on porous solids will be investigated, including incremental approaches for the sequential surface-grafting of both catalyst and acidic co-catalyst. These systems will be evaluated for their ability to catalyze Michael addition reactions, leading to chiral products with two stereocenters. In order to shed light on the reaction machinery, a computational approach combined with advanced ESI-MS techniques will be adopted. The combination of experimental evidences, spectroscopic analyses and computational rationalizations would lead to an iterative process enabling a faster convergence to optimal reaction conditions.
Like all scientists working with heterogeneous and flow catalytic processes, we too expect our results to go towards more sustainable green processes. In particular, each line of the research proposal presents innovative claims and is focused on single enantiomer production. We expect to complete the project in a time period time spanning 12-18 months. In WF1, the optimization of combined supported catalyst/cocatalyst for the cinchona alkaloid class and the preparation of supported chiral diamine has never been actually presented. The new materials are expected to have long term stability and good synthetic performances. In WF2 the flow reactors can be coupled with a fast enantioselective separation method (i.e. UHPLC) for on-line monitoring of reaction progress. From the mechanistic point of view, line WF3, the activation of carbonyl groups via enamine/iminium ion represents an ideal candidate for MS investigation due to the presence of ionic and easy ionizable intermediates. There are only few mechanistic studies investigating the activation mode of those catalysts and ESI-MS approach has never been used in this context. Computational studies will support the interpretation of data obtained by mass spectroscopy and, in a second step, they will be crucial to complete the stereochemical characterization of the obtained single enantiomers. We believe this project will provide essential insights to elucidate the mechanism of catalysis of chiral primary mono- and di-amines, thus opening the possibility for developing new and improved reactions. Moreover, a more ambitious goal is the realization of a solid supported organic/metallorganic catalyst to address stereocontrol at multiple stereogenic elements.