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CAOS group (Catalytic Applications in Organic Synthesis - for Fine Chemicals)  

CAOS Group

RESEARCH GROUP
CAOS group (Catalytic Applications in Organic Synthesis - for fine chemicals)

 

Principal InvestigatorProf. Egle Beccalli, Prof. Elisabetta Rossi
MembersProf. Giorgio Abbiati, Prof. Egle Beccalli, Dr. Giorgio Facchetti, Prof. Raffaella Gandolfi, Dr.ssa Isabella Rimoldi, Prof. Elisabella Rossi, Dr.ssa Valentina Pirovano

   

DESCRIPTION

The main interest of the research group deals with the development of new synthetic approaches based on catalysis, with particular devotion to homogenous catalysis promoted by transition metals and biocatalysis mediated by both whole cells or isolated enzymes. Among the transition metals, ruthenium, rhodium, iridium, palladium, platinum, copper, silver and gold are the main subjects of the investigations. The interest of the group is manifold and includes both design, preparation, and isolation of new catalysts, and their use in the organic synthesis, with particular (but not exclusive) reference to the synthesis and functionalization of nitrogen- and oxygen-containing heterocycles. From a methodological point of view, great importance is given to the study of processes characterized by a high degree of sustainability, such as domino and multicomponent reactions, the use of alternative solvents characterized by a reduced environmental impact, and the use of unconventional energy sources such as microwaves and ultrasounds. The complete chemical-physical characterization of the synthesized molecules represents a fundamental step of the research projects. Finally, as a corollary and conclusion of the research projects, in some cases, the potential applications in the life sciences and material sciences of the synthesized molecules are investigated.

The studies are mainly methodological rather than "product-oriented". Usually, the main goals are not to synthesize a particular molecule, but to develop robust, sustainable, and innovative approaches capable of promoting a catalytic or synthetic process or increasing its efficiency, thus paving the way for easy preparation of libraries of compounds of potential interest in biology and/or in the material chemistry.

In the group, there are three main research lines:

 

1) Development of new chiral catalysts for the asymmetric synthesis of pharmaceutically relevant intermediates and biologically active molecules 

Our research interests have been focused on the synthesis and characterization of transition metal complexes endowed with a stable chiral configuration at the metal centre, whose enantiopure configuration could be exploit as a realistic probe to afford useful information about the variations in the chirality of the complex along the different stages in its catalytic cycle. Indeed, a great effort is devoted to a tailored design of the chiral ligands employed for the preparation of the complexes with a special interest in the synthesis of enantiopure phosphorus containing ligands and diamines, either characterized by atropoisomerism or featuring a stereogenic sp3 carbon atom, or both with a mixed source of chirality. Transition metal catalysts and enzymes possess unique and often complementary properties and in the last decades researchers tried to combine the structure and the reactivity of metals and peptides in a so-called hybrid catalyst. In this context, a transition metal complex is embedded in a biological environment made up of proteins (but not exclusively), as well as short peptides, chiral by definition. Different anchoring strategies of the metal moiety (“first coordination sphere”) into the biological entity (“second coordination sphere”) have been pursued based on suitable linkers, with the biological counterpart able, in principle, to afford exquisite levels of enantioselectivity within the catalytic reaction. These hybrid catalysts proved robust and reactive also in different aqueous media and under green reactions conditions thus offering the possibility to expand the scope of organic reactions in which they could be applied. Their main field of application spans from the synthesis of pharmaceutically and industrially relevant intermediates to chiral active ingredients through different types of asymmetric homogeneous catalytic reactions such as hydrogenation, transfer hydrogenation and hydroformylation.

The availability of different catalytic approaches for enantio- and diastereoselective catalysis is a challenging topic in chemical synthesis, especially when the formation of multiple stereogenic centers takes place during the reaction. As an additional approach to the transition metal-based systems, our research field comprises also an accurate selection of biocatalysts among different strains of yeasts and molds available in our laboratories, used either as whole cells or isolated enzymes, for the enatio- and diasteroselective synthesis of biologically active molecules, often complementary in terms of absolute configuration to the ones obtained by homogeneous metal catalysis, obtained starting from pro-chiral substrates under green reaction conditions.

 

2) Organic synthesis promoted by coinage metals

This research line deals with developing new approaches for the synthesis of organic molecules (with particular reference to oxygen- and nitrogen-containing heterocyclic compounds, also as polycondensed structures) with the aid of metal catalysis. In particular, the metals subject of the studies are salts and complexes of gold and silver. Gold and silver are coinage metals characterized by unique peculiarities. Among the transition metals, gold is the most affected by the relativistic effect, which makes it able to efficiently promote chemical transformations that are difficult to obtain in other ways. Silver, with its dual σ-filic and π-filic activity, can activate simultaneously different reactive centres, including unsaturated carbon-carbon systems (alkenes, alkynes, allenes, etc.) and unsaturated carbon-heteroatom systems (carbonyls, imines, nitriles, etc.).

Due to these peculiarities, the starting materials used to develop the transformations promoted by coinage metals are mainly unsaturated systems variously functionalized and/or characterized by the presence of a reactive group in a proximal position. The subjects of study are both the reactions that lead to the formation of the heterocycle (cycloadditions, cyclizations, annulations, cycloisomerization) and the transformations aimed at functionalizing the heterocycle in a chemo-, regio-, and stereo-selective fashion. The most studied molecules are nitrogen-containing heterocycles such as indoles, quinolines, and isoquinolines, and oxygen-containing ones such as isochromenes, isocoumarins, and isobenzofurans.

How these transformations are planned and carried out are crucial factors for the success of the research and the overall sustainability of the processes becomes a decisive argument. Therefore, from a methodological point of view, cascade and multicomponent approaches are favoured, which allow the formation of multiple bonds in a single operational step without the addition of additional reagents and catalysts, without isolation of the intermediates, and without changing the reaction conditions. This allows an advantage from both an economic and an ecological point of view. Mild reaction conditions are preferred and when heating is necessary, the possibility of using high-performance energy sources such as microwaves is always evaluated and preferred. It is well known that microwaves can reduce reaction times and hamper the formation of by-products, beside an overall increase of the reaction yields. The possibility to employ alternative and more sustainable solvents are investigated. In particular, some transformations are studied in DES (Deep Eutectic Solvents). DES are the new frontier of ionic liquids, from which they differ for the nature of the bonds involved in the formation of the eutectic, for the straightforward preparation and the lower toxicity and environmental impact of their components. Depending on their structure, DES also have the peculiarity of being able to behave not only as solvents (innocent-DES) but also as reagents and/or catalysts (active-DES), so further increasing the degree of efficiency and sustainability of the processes under investigation .

 

3) C-H activation through the transition-metals catalysis

The transition-metals catalysis allowed a great development in organic synthesis, especially for the preparation of different classes of heterocycles. However, the majority of the new bonds arises from previously activated substrates. The current challenge consists on the use of non-activated substrates, exploiting the C-H activation principle through the transition-metal catalysis to create new bonds. The process can affect the synthesis of carbo- and heterocyclic compounds through the formation of C-C, C-N and/or C-O intramolecular bonds and lead to different functionalized cyclic systems involving domino or cascade reactions. In these processes, Pd(II) complexes are normally used with an oxidizing agent in order to bring the catalyst back to its reactive oxidative state. Then the synthetic strategy is diversified according to the possible variables involved: in addition to the catalyst and the solvent, the oxidizing agent could also have a crucial role. It is possible to obtain different products, starting from the same substrate and using different catalysts (platinum or copper alternatively to the palladium) or simply different reaction conditions, resulting in divergent synthetic paths, following alternative or parallel reaction mechanisms.

 

 

ONGOING RESEARCH COLLABORATIONS


• Scuola Normale Superiore di Pisa (Dr. M. Fusè);
• Università della Calabria, Dipartimento di Chimica e Tecnologie Chimiche – CTC (Prof.ssa I. Aiello);
• Università di Padova, Dipartimento di Scienze Farmaceutiche e Farmacologiche (Prof. N. Ferri, Prof.ssa L. Dalla Via);
• Università degli Studi de L’Aquila, Dipartimento di Scienze Fisiche e Chimiche, (Prof. A. Arcadi);
• University of Oviedo, Department of Organic and Inorganic Chemistry (Prof. J. M. Gonzàlez, Dr. R. Vicente);
• Università di Milano, Dipartimento di Chimica (Prof. A. Caselli, Prof. S. Rizzato).
• Università degli Studi di Parma, Dipartimento di Medicina e Chirurgia (Prof. L. Ronda)
• Università di Chieti-Pescara “G. D’Annunzio”, Dipartimento di Farmacia (Dr. M. Tiecco)
• Università di Catania (Prof. A. Chiacchio)
• Sorbonne Universités, UPMC Univ Paris 06 (Prof. G. Poli).

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