Dottorato in SCIENZE CHIMICHE

Titolo della tesi: Total synthesis of natural products: synthesis of key intermediates towards (-)-parthenolide and kinamycin F

Total synthesis of natural products has become, since its development around the half of the 19th century, one of the most interesting and challenging ways in obtaining bioactive compounds originating from different kind of natural matrixes. In particular, a way to obtain (-)-Parthenolide, a sesquiterpene lactone of the germacranolide class originating from the plant Tanacetum parthenium (Asteraceae family), and kinamycin F have been studied since their promising application as treatment for different diseases. The first one showed marked antitumoral properties and has been studied as promising treatment against endometriosis1, a severe and highly diffuse feminine disease which causes chronic symptoms2. Therefore, by proposing a highly stereoselective retrosynthetic pathway, the first stereoselective total synthesis of (-)-parthenolide has been approached with a synthetic route characterized by the least number of steps, compared to the few already existent semisynthesis3, and enantio and diastereoselectivity through 4 key steps: an olefin metathesis, a diastereoselective epoxidation, a diastereoselective iodolactonization, and an enantioselective conjugate addition. Regarding kinamycin F, it is known that kinamycins are bacterial secondary metabolites belonging to the tetrahydrofluorenone class of natural products. They contain a [6-5-6] ring scaffold and possess a broad range of biological properties, marked anti-cancer activity, and may be obtained directly from bacteria. However, this method provides access only to small amounts of compound, thus not enough to carry out in-depth studies on the development of kinamycin F and its possible derivatives displaying cytotoxic behaviour4. Hence, the development of a robust and diversity-oriented synthetic route to kinamycin F in order to also access different analogues for biological screening purposes and applications as been attempted. The newly proposed total synthesis revolves around a Pd-catalyzed domino cyclization reaction developed in a previous work on similar substrates5. In addition to this reaction, key steps in this sequence involve enzymatic arene oxidation, selective reduction of an amide directing group to a methyl, as well as the installment of two additional hydroxy-substituents via epoxidation and hydrolysis. [1] Freund, R. R. A.; Gobrecht, P.; Fischer, D.; Arndt, H. D. Advances in chemistry and bioactivity of parthenolide. Nat Prod Rep 2020, 37 (4), 541-565. DOI: 10.1039/c9np00049f. [2] Ministero della Salute, Endometriosi. 2021. https://www.salute.gov.it/portale/donna/dettaglioContenutiDonna.jsp?id=4487&area=Salute%20donna&menu=patologie. [3] Li, L.; Pan, X.; Guan, B.; Liu, Z. Stereoselective total synthesis of (±)-parthenolide and (±)-7-epi-parthenolide. Tetrahedron 2016, 72 (29), 4346-4354. DOI: 10.1016/j.tet.2016.05.074. [4] Herzon, S. B. The kinamycins. In Total Synthesis of Natural Products: At the Frontiers of Organic Chemistry, Li, J. J., Corey, E. J. Eds.; Springer Berlin Heidelberg, 2012; pp 39-65 [5] P. Dunås, A. J. Paterson, G. Kociok-Köhn, M. Rahm, S. E. Lewis, N. Kann, Chem. Commun. 2021, 57, 6518-6521