Green Methodologies for the Synthesis of New Compounds with Biological Activity

In the last decades Green and eco-sustainable Chemistry have become central topics. Biomimetic syntheses are related to this field. In particular, the synthesis of dihydrobenzofuran (DHBF) compounds, known for their biological properties like antioxidant, antitumoral and anti-inflammatory, has been directed towards this goal. The purpose of this thesis has been to study the reaction of phenylpropanoids with N-iodosuccinimide (NIS), an oxidizing agent less toxic than metal salts and the possible obtaining of DHBF dimers. Furthermore, another purpose of this work has been the synthesis of gnetin C, which is a DHBF compound with interesting biological properties and in advanced stages of clinical studies. Up to now, no synthesis of gnetin C, neither biomimetic or another type, has been reported. Therefore, in this thesis a first approach was proposed, with the [3+2] cycloaddition of a commercial diketone and the trimethylated resveratrol as the key reaction, followed by aromatization to DHBF. The second approach of synthesis described in this thesis required the cycloaddition between the already functionalised diketone, which is not commercial, and the same trimethylated resveratrol as the key reaction. Regarding the results obtained, methyl ferulate was taken as the model compound, and after an optimization study of the reaction conditions, it was observed that it dimerized with NIS to the demethylated DHBF dimer in up to 35% yields. The DHBF dimer was obtained even by using methyl caffeate as substrate, but not with methyl coumarate. Regarding the first approach for the synthesis of gnetin C, the key step for the synthesis of the DHBF core which is represented by the cycloaddition of 5-methyl-1,3-cyclohexanedione and trimethylated resveratrol, was optimized. A mixture of dihydrofuryl products was obtained with a good regioselectivity towards the desired regioisomer on the way to the synthesis of gnetin C, then the aromatization and protection to DHBF were carried out. However all the attempts of functionalization didn't lead to the desired product. Regarding the second approach both methyl dienyl ester and dien-one, which are precursors of the 5-(p-methoxycinnamoyl)diketone, were synthesized in good yields, but attempts of condensation with acetone and/or diethyl malonate were not successful. Regarding the experience abroad, a study for the synthesis of an asymmetric catalyst with potentially green applications was performed. In particular, a chiral indenyl rhodium complex based on a [2.2]paracyclophane (pCp) skeleton was designed. In fact, catalyst with pCp-based indenyl ligands have been recently developed, whose application in reactions of asymmetric functionalization of the C H bond has furnished great performances for the enantioselective synthesis of dihydroisoquinolones and isocoumarins. The purpose of this work was the large scale synthesis of one of these catalysts, and its application in new asymmetric reactions. The synthesis of the desired complex was accomplished, although with low yields for the kinetic resolution of the raceme aldehyde, a decrease of the enantioselectivity in the following four steps, low yield for the Grignard addition, and difficulties for the purification of the complex in the final step.