Total syntheses of the tylophora alkaloids cryptopleurine, (-)-antofine, (-)-tylophorine, and (-)-ficuseptine C.
A concise, efficient and modular approach to the tylophora alkaloids is described, a family of potent cytotoxic agents that are equally effective against drug sensitive and multidrug resistant cancer cell lines. The advantages of the chosen route are illustrated by the total syntheses of the phenanthroquinolizidine cryptopleurine (1) and the phenanthroindolizidines (-)-antofine (2), (-)-tylophorine (3), and their only recently isolated congener (-)-ficuseptine C (4). The key steps consist in a Suzuki cross-coupling between a (commercial) boronic acid and a simple aryl-1,2-dihalide followed by elaboration of the resulting products into the corresponding 2-alkynyl-biphenyl derivatives 27, 33, 41 and 46. The latter undergo PtCl2-catalyzed cycloisomerizations with formation of the functionalized phenanthrenes 28, 34, 42 and 47, which were transformed into the targeted alkaloids by a deprotection/Pictet-Spengler annulation tandem. Due to the flexibility and robust character of this approach, it might enable a systematic exploration of the pharmacological profile of this promising class of bioactive natural products.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Kennedy
Jason W J
JW
D000470:Alkaloids / Q000138:chemical synthesis*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis; D007211:Indoles / Q000138:chemical synthesis*; D007212:Indolizines / Q000138:chemical synthesis*; D010616:Phenanthrenes / Q000138:chemical synthesis*; D010618:Phenanthrolines / Q000138:chemical synthesis*
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D007212:Indolizines; D010616:Phenanthrenes; D010618:Phenanthrolines; C473343:antofine; C503001:ficuseptine C; C007160:cryptopleurine; C004218:tylophorine