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Ab initio Statics and Molecular Dynamics Simulation of Olefin Metathesis Catalysts for pharmacological purposes

Final Report Summary - COMPUTEDRUG (Ab initio Statics and Molecular Dynamics Simulation of Olefin Metathesis Catalysts for pharmacological purposes)

The project “Ab initio Statics and Molecular Dynamics Simulation of Olefin Metathesis Catalysts for pharmacological purposes”, with the acronym “ComputeDRUG” has given computational insight into the olefin metathesis field, with a clear outline that consists of the rationalization of the available catalysts, and from their better knowledge to go further to propose new generations of catalysts that solve some of their present issues such as the activation, cost, and stability. Furthermore, due to the presence of olefin metathesis reactions in the synthesis of drugs, the subject of the present project has been extremely relevant at medical research level, becoming a key point in the advance of research for improving the synthesis of drugs containing a macrocycle, for example useful to fight against hepatitis. The project has integrated the whole range of innovation – from advanced research to industrial exploitation –, providing an environment in which scientific results can rapidly be transformed into products and processes, which benefit society solving diseases or because of the synthesis of new kinds of materials, such as polymers, for example. The systematic study of the present catalysts as well as modified ones, or even new generations of catalysts has been tested during the last four years getting fundamental knowledge to understand better the role of olefin metathesis catalysts: getting answers of how the catalysts are activated in the initiation part; thanks to the steric maps through a web server which is user-friendly for any computational or experimental chemist, as well, it is possible to predict now which architecture of the olefin metathesis catalyst must adopt, bearing in mind a particular alkene substrate. Here the relative stability of the metallacycle has been found to be key, showing that when this intermediate is clearly energetically disfavoured the olefin metathesis catalytic reaction does not take place in normal conditions. This descriptive knowledge based on studies in existing catalysts has allowed the prediction of new generation of catalysts, removing the Ru by the no toxic and cheaper Fe, as well as the substitution of the NHC ligand by a second ylidene ligand.
Most of the projects have involved a mechanistic overview of the reaction pathway in order to unravel the rate-determining step of each reaction. There have been two main kinds of reactions studied related to olefin metathesis. On one hand the study of the activation of olefin metathesis catalysts has driven to a clear understanding of the value of the catalyst. Take for instance, only the relative stability between the so-called central metallacycle intermediate and its precedent coordination intermediate is enough to predict if an olefin metathesis proceeds with such a particular reaction. On the other hand, the careful study of deactivation processes has helped to rationalize which kind of substituents are not suitable for olefin metathesis catalysis, because when bearing them the catalyst decomposes. Thus, studying the rate determining step of the decomposition reactions is enough to know if they will be competitive with the regular olefin metathesis reaction, and in silico predictions to increase the barriers for these undesired parallel reactions have been displayed throughout the whole project. Thus, the computational in silico calculations now are enough to test a new catalyst, and compare its activity with previous existing ones, saving experimental resources in the syntheses of hundreds of catalysts which would not be that active.
Overall, this project has brought light into the mature olefin metathesis field, which is nowadays based on getting particular solutions for each problem, after showing that there is not only a catalyst that it is useful for all kind of olefin metathesis reactions.
Last but not least, the results originated from this project, published in international journals as well as presented in highly recognized world level congresses, have helped to include University of Girona, and thus Spain, in the world computational olefin metathesis research map, and strength the know-how in the field as well as share it in University of Girona. And furthermore, this new know-how has been extended in several projects including gold catalysis, carbon dioxide fixation, and hydrogenation.