Enantioselective total synthesis of (+)-ottelione A, (-)-ottelione B, (+)-3-epi-ottelione A and preliminary evaluation of their antitumor activity.
Enantioselective total synthesis of (+)-ottelione A (1) and (-)-ottelione B (2), novel and potent antitumor agents from a freshwater plant, and (+)-3-epi-ottelione A (3), the earlier proposed stereostructure of 1, was efficiently achieved starting from the known tricyclic compound 10. The synthesis involved the following key steps: i) coupling reactions of aldehydes 8 and 9 with the aromatic portion 7 (8+7-->15 and 9+7-->27), ii) base-induced hemiacetal-opening/epimerization reactions of the cyclic hemiacetals 6 and 27 (6-->17 and 27 a-->26 a), and iii) Corey-Winter's reductive olefination of the cyclic thiocarbonates 21 and 36 (21-->22 and 36-->37). The present total synthesis fully established the absolute configuration of these natural products. The cell growth inhibition profile, COMPARE analysis, and tubulin inhibitory assay of (+)-3-epi-ottelione A (3) and its O-acetyl derivative 24 demonstrated that these unnatural substances could be prominent lead compounds for the development of anticancer agents with a novel mode of action.
Araki
Hiroshi
H
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama, Japan.
Inoue
Munenori
M
Suzuki
Takeyuki
T
Yamori
Takao
T
Kohno
Michiaki
M
Watanabe
Kazuhiro
K
Abe
Hideki
H
Katoh
Tadashi
T
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D003512:Cyclohexanones; D014404:Tubulin; C468748:ottelione A; C468747:ottelione B