(-)-Parthenolide (figure 1, compound 1), a sesquiterpene lactone of the germacranolide class originating from the plant Tanacetum parthenium (Asteraceae family, figure 1.A)1, has been studied as promising treatment against endometriosis2, a severe and highly diffuse feminine disease which causes chronic symptoms3. Moreover, it also shows strong antitumoral properties4, similar to those of the chemotherapic 5-azacytidine, and high selectivity towards target tissues2. Therefore, by proposing a highly stereoselective retrosynthetic pathway (figure 1), the first stereoselective total synthesis of (-)-parthenolide has been approached. The synthetic route will be characterized by the least number of steps, compared to the few already existent semisynthesis5, and enantio and diastereoselectivity will be possible through 4 key steps (figure 1, marked in red): an olefin metathesis (figure 1, B), a diastereoselective epoxidation (figure 1, C), a diastereoselective iodolactonization (figure 1, D), and an enantioselective conjugate addition (figure 1, E). Moreover, compound 4 will be used as common intermediate in two different steps, thus improving the synthesis reactants usage and resources waste for a greener perspective. [1] (EMA), E. M. A. Assessment report on Tanacetum parthenium (L.) Schultz Bip., herba. (HMPC), C. o. H. P., Ed.; 8 July 2020. [2] 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. [3] Ministero della Salute, Endometriosi. 2021. https://www.salute.gov.it/portale/donna/dettaglioContenutiDonna.jsp?id=4487&area=Salute donna&menu=patologi e. [4] Ghantous, A.; Sinjab, A.; Herceg, Z.; Darwiche, N. Parthenolide: from plant shoots to cancer roots. Drug Discov Today 2013, 18 (17-18), 894-905. DOI: 10.1016/j.drudis.2013.05.005. [5] 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
Total synthesis of (-)-parthenolide through a stereoselective approach / Celio, L.; Rendeli, D.; Di Paolo, J.; Vetica, F.; Migneco, L. M.; Leonelli, F.. - (2023). (Intervento presentato al convegno XLI Convegno Nazionale della Divisione di Chimica Organica, CDCO Roma 2023 tenutosi a Roma; Italy).
Total synthesis of (-)-parthenolide through a stereoselective approach
L. Celio
;J. Di Paolo;F. Vetica;L. M. Migneco;F. Leonelli
2023
Abstract
(-)-Parthenolide (figure 1, compound 1), a sesquiterpene lactone of the germacranolide class originating from the plant Tanacetum parthenium (Asteraceae family, figure 1.A)1, has been studied as promising treatment against endometriosis2, a severe and highly diffuse feminine disease which causes chronic symptoms3. Moreover, it also shows strong antitumoral properties4, similar to those of the chemotherapic 5-azacytidine, and high selectivity towards target tissues2. Therefore, by proposing a highly stereoselective retrosynthetic pathway (figure 1), the first stereoselective total synthesis of (-)-parthenolide has been approached. The synthetic route will be characterized by the least number of steps, compared to the few already existent semisynthesis5, and enantio and diastereoselectivity will be possible through 4 key steps (figure 1, marked in red): an olefin metathesis (figure 1, B), a diastereoselective epoxidation (figure 1, C), a diastereoselective iodolactonization (figure 1, D), and an enantioselective conjugate addition (figure 1, E). Moreover, compound 4 will be used as common intermediate in two different steps, thus improving the synthesis reactants usage and resources waste for a greener perspective. [1] (EMA), E. M. A. Assessment report on Tanacetum parthenium (L.) Schultz Bip., herba. (HMPC), C. o. H. P., Ed.; 8 July 2020. [2] 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. [3] Ministero della Salute, Endometriosi. 2021. https://www.salute.gov.it/portale/donna/dettaglioContenutiDonna.jsp?id=4487&area=Salute donna&menu=patologi e. [4] Ghantous, A.; Sinjab, A.; Herceg, Z.; Darwiche, N. Parthenolide: from plant shoots to cancer roots. Drug Discov Today 2013, 18 (17-18), 894-905. DOI: 10.1016/j.drudis.2013.05.005. [5] 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.2016.05.074I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
