Organic chemistry has seen a tremendous growth over the past decades and nowadays it is routinely used for a variety of applications in countless fields. Nevertheless, a major concern that is hindering its development is the negative impact that organic synthetic methodologies may have on the environment. Therefore, great effort has been devoted to the development of novel efficient and sustainable synthetic approaches. In this scenario, catalysis has played a crucial role in the preparation of organic molecules as drugs, natural products, and agrochemicals to improve the greenness of a synthetic process. Although it moved its first steps in organic chemistry in the 18th century, catalysis is still considered a hot topic, especially because it stood out as a valuable and efficient tool to access economical, energy-saving, and sustainable chemical processes. The aim of this doctoral thesis is to devise and employ a variety of novel catalytic approaches as means to efficiently access relevant pharmacologically active molecules. With this aim in mind, we developed different methodologies to improve the sustainability of the proposed synthetic processes without sacrificing efficiency. A cascade cyclocarbopalladation of the readily available aryl/alkyl-substituted propargylic amides followed by Suzuki–Miyaura coupling with arylboronic acids or aminopalladation reacting with 2-alkynyltrifluoroacetanilides allowed an efficient regio- and stereoselective synthesis of dihydroisoquinolinones differently substituted. The usefulness of this cascade approach is determined by the high number of bonds formed in a single synthetic step, that leads to the increased structural complexity of desired products and to the improvement of the greenness of the whole process, avoiding numerous subsequent purification steps and reducing wastes. Then, a novel metal-free protocol to perform N-alkylation reactions of a wide variety of amine substrates was developed. This mild boron Lewis acid-catalysed synthetic methodology gives access to a broad range of pharmacologically appealing N-alkylated products in good to excellent yields. Moreover, a fruitful collaboration between Dr Melen’s and Prof. Dr Carlone’s groups was established to develop convenient methods for the quick construction of chiral boron Lewis acids. With this purpose, the synthesis of several chiral ligands was carried out to pave the way to a novel asymmetric metal-free approach. Exploiting organocatalysis as greener catalytic strategy, a novel and safe reaction protocol for the enantioselective enamine-catalysed addition of acetaldehyde to nitroalkenes was performed. This protocol makes use of a safe masked acetaldehyde to access important intermediates to Active Pharmaceutical Ingredients (APIs) improving the industrial feasibility of the entire process. Using water as a reaction medium allows us to further improve this synthetic protocol. Crucial to the success of this approach was the application of chemometrics-assisted ‘Design of Experiments’ (DoE) optimisation during the development of the presented approach. DoE allows to investigate the chemical space in a rational way, reducing the number of the experiments. Moreover, a library of phosphoric acids was synthesised to develop an organocatalysed eco-friendly approach to the enantioselective cyclobutane-containing molecules preparation. An efficient alternative protocol for the synthesis of a valuable API precursor developed in collaboration with the pharmaceutical industry Dipharma is also reported. We designed and developed an alternative approach to improve the well-established methodology by limiting the waste production as much as possible exploiting immobilised catalysts. The last catalytic methodology investigated is a combination of the previous ones, known as synergistic catalysis. A critical review about current and past literature is reported.

Development of novel and sustainable catalytic strategies for the synthesis of pharmacologically interesting compounds / Nori, Valeria. - (2022 May 06).

Development of novel and sustainable catalytic strategies for the synthesis of pharmacologically interesting compounds

NORI, VALERIA
2022-05-06T00:00:00+02:00

Abstract

Organic chemistry has seen a tremendous growth over the past decades and nowadays it is routinely used for a variety of applications in countless fields. Nevertheless, a major concern that is hindering its development is the negative impact that organic synthetic methodologies may have on the environment. Therefore, great effort has been devoted to the development of novel efficient and sustainable synthetic approaches. In this scenario, catalysis has played a crucial role in the preparation of organic molecules as drugs, natural products, and agrochemicals to improve the greenness of a synthetic process. Although it moved its first steps in organic chemistry in the 18th century, catalysis is still considered a hot topic, especially because it stood out as a valuable and efficient tool to access economical, energy-saving, and sustainable chemical processes. The aim of this doctoral thesis is to devise and employ a variety of novel catalytic approaches as means to efficiently access relevant pharmacologically active molecules. With this aim in mind, we developed different methodologies to improve the sustainability of the proposed synthetic processes without sacrificing efficiency. A cascade cyclocarbopalladation of the readily available aryl/alkyl-substituted propargylic amides followed by Suzuki–Miyaura coupling with arylboronic acids or aminopalladation reacting with 2-alkynyltrifluoroacetanilides allowed an efficient regio- and stereoselective synthesis of dihydroisoquinolinones differently substituted. The usefulness of this cascade approach is determined by the high number of bonds formed in a single synthetic step, that leads to the increased structural complexity of desired products and to the improvement of the greenness of the whole process, avoiding numerous subsequent purification steps and reducing wastes. Then, a novel metal-free protocol to perform N-alkylation reactions of a wide variety of amine substrates was developed. This mild boron Lewis acid-catalysed synthetic methodology gives access to a broad range of pharmacologically appealing N-alkylated products in good to excellent yields. Moreover, a fruitful collaboration between Dr Melen’s and Prof. Dr Carlone’s groups was established to develop convenient methods for the quick construction of chiral boron Lewis acids. With this purpose, the synthesis of several chiral ligands was carried out to pave the way to a novel asymmetric metal-free approach. Exploiting organocatalysis as greener catalytic strategy, a novel and safe reaction protocol for the enantioselective enamine-catalysed addition of acetaldehyde to nitroalkenes was performed. This protocol makes use of a safe masked acetaldehyde to access important intermediates to Active Pharmaceutical Ingredients (APIs) improving the industrial feasibility of the entire process. Using water as a reaction medium allows us to further improve this synthetic protocol. Crucial to the success of this approach was the application of chemometrics-assisted ‘Design of Experiments’ (DoE) optimisation during the development of the presented approach. DoE allows to investigate the chemical space in a rational way, reducing the number of the experiments. Moreover, a library of phosphoric acids was synthesised to develop an organocatalysed eco-friendly approach to the enantioselective cyclobutane-containing molecules preparation. An efficient alternative protocol for the synthesis of a valuable API precursor developed in collaboration with the pharmaceutical industry Dipharma is also reported. We designed and developed an alternative approach to improve the well-established methodology by limiting the waste production as much as possible exploiting immobilised catalysts. The last catalytic methodology investigated is a combination of the previous ones, known as synergistic catalysis. A critical review about current and past literature is reported.
Development of novel and sustainable catalytic strategies for the synthesis of pharmacologically interesting compounds / Nori, Valeria. - (2022 May 06).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11697/190321
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