title: Enantiocontrolled total synthesis of (-)-mersicarpine.
abstract: A racemic synthesis of mersicarpine (1) was achieved by the Mizoroki-Heck reaction and a DIBALH-mediated reductive ring-expansion reaction. Based on a first-generation synthesis, a second-generation enantiocontrolled total synthesis of (-)-mersicarpine (1) was achieved by an 8-pot/11-step sequence in 21% overall yield from commercially available 2-ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d'Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six-membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH-mediated reductive ring-expansion reaction, gradually increasing the reaction temperature and in situ-protection of the nitrogen in an oxygen-sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high-yielding process. With these methodologies, the short-step and efficient synthesis of (-)-mersicarpine was accomplished. Several synthetic efforts are also described.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Iwama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Okano
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tokuyama
keywords: mersicarpine; natural products; ring expansion; synthetic methods; total synthesis