The here proposed project aims, in its first stage, to investigate new fields of application of the not too exploited, although extremely powerful, branch of chromatography, known by the term `Dynamic Chromatography¿ (DC), currently adopted exclusively for the purpose of studying kinetic aspects characterizing both steric and constitutional isomerization of organic molecules, typically promoted by acid or basic conditions. More in particular, to date, such a typology of isomerizations have always been analyzed performing DC determinations with the on-column process evolving in equilibrium condition. Thus, one of the pursued goals will be that to promote more generic on-column organic reactions, far from their condition of equilibrium, and to analyze the so resulting nonclassic dynamic chromatograms by suitable profile-simulation, which will allow to achieve the kinetic quantities of the investigated reactions. As a variant of this approach, it is also planned to bound on the silica of a HPLC column one of the reacting species, selected with condition to be easily restored to its initial state by suitable chemical treatment at the end of the analyzed reaction. In this way, the so modified HPLC column will be able to act as a reactor towards suitable injected species. More classic derivatization of silica with organic catalysts will also be carried out with the intent to prepare original flow-reactors. Finally, classical DC determinations and theoretical calculations are also planned to be performed in aim to assess the free energy activation barriers, deltaG#, which oppose the enantiomerization of tricyclic molecules endowed with planar chirality, commonly employed as drugs in racemate version. In this way, will be possible to select the species characterized by low deltaG# barriers, and design for these not too extensive chemical modifications, able to strongly increase the deltaG# values and, therefore, make possible their existence as single stable enantiomers.
As already reported in the previous sections, the present project will put the bases to allow the achievement of at least four objectives showing innovative character in international context, in a time period reasonably included in the proposed 18 months. The first is represented by the concrete possibility to extend application of the powerful DC technique to the study of reactions different to the specific case of constitutional or conformational isomerizations, with the first example focused on the study of REDOX reactions. The second target will be represented by the preparation of HPLC reactors with selectors directly involved in on-column reactions not as catalysts (i.e., preparation of reactors, not flow-reactors), but as direct participants of reactions to by studied, which will be able to be restored to their initial state by a final treatment performed with mild experimental conditions. Also in this case it is planned that the first example will involve REDOX reactions, with oxidizing species bonded to the SMs. From these HPLC-reactors will be obtained nonclassical Dyn-Chrs to be properly simulated, and so, the kinetic information relevant to studied reactions. However, as innovative aspect, it will also be taken into considerations preparation of classic flow-reactors characterized by the binding on ASs of new catalytic species, endowed with chiral diaminic or organic/metallorganic structures able to address stereocontrol at multiple stereogenic elements, a really ambitious, but possible, target. The achievement of third goal will be instead focused on the development of a new procedure able to guarantee an extensive deprotonation of SMs, with an expected percentage of involved silanols close to 100%, never reached until now, to our knowledge. In this way, the so obtained ASs should guarantee effective derivatizations, with very high degree of loading of the desired selectors. The fourth final objective will be addressed to a systematic analysis of stereolability of tricyclic drugs, nowadays administered as racemates because of the marked tendence of the relevant enantiomers to invert their chirality plane. A suitable not too extensive chemical modification of their structure will be designed by molecular modeling analysis, follewed by experimental confirmation of the achieved stereostability and semipreparative enantio-discrimination of the relevant optical isomers. This will be an interesting example of how important it is not to neglect forms of molecular chirality due to stereogenic elements other than centers of asymmetry
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