The project targets the design and realization of improved catalytic batch and flow systems for enantioselective synthesis, together with chiroptical investigation of single enantiomers for absolute configuration assignments. These two aspects combine in a useful platform enabling production and characterization of single enantiomers using greener procedures aiming at process intensification (immobilized organocatalysts, flow mode reactions) and straightforward combinations of experimental and computational techniques (ECD, VCD, ORD). The project toolbox includes: mesoporous silica, monolithic polymers with dual micro- and meso-porosity, all with tunable surface chemistry and amenable for chemical functionalization. Chiral organonocatalysts based on chinconan alkaloids and acidic co-catalysts will be exploited as privileged structures for the preparation of porous catalytic systems to be used in either batch or flow mode processes. Innovative mechanistic investigations will rely on electrospray ionization mass spectrometry ESI-MS , a now well established tool for screening the reactivity of catalysts, monitoring organic and organometallic reactions by detection of reactants, intermediates and products and eventually elucidation of reaction mechanisms .Experimental data (reaction yields, enantiomeric excess, absolute configuration, intermediates observed by ESI-MS) will be rationalized and used to generate improved and refined systems.
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 is focused on single enantiomer production and it is expected to be completed during the project time spanning 12-18 months. In L1, the synthesis of combined supported catalyst/cocatalyst for the cinchona alkaloid class has never been actually presented. The new materials are expected to reduce the post-reaction work-up by one-step (recovery of cocatalyst). In L2 the flow version of the system foresees an on-line monitoring of reaction progress, that can be realized by using a fast enantioselective separation method (i.e. UHPLC) coupled to the exit of flow reactor. In addition, reuse of catalyst and long use of flow reactor allow small amount of organocatalyst to be synthetized.
From the mechanistic point of view (line L3), 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. In literature, there are 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 the second step, they will be crucial to complete the stereochemical characterization of obtained single enantiomer.
We believe this project will provide essential insights to elucidate the mechanism of catalysis of cinchona-based primary amines, thus opening the possibilities 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.