Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

Journal of Natural Medicines - Tập 70 - Trang 302-317 - 2016
Yoshihiko Noguchi1,2, Tomoyasu Hirose1,2, Aki Ishiyama1,2, Masato Iwatsuki1,2, Kazuhiko Otoguro1, Toshiaki Sunazuka1,2, Satoshi Ōmura1
1Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan
2Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan

Tóm tắt

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin–Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

Tài liệu tham khảo

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