Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid.
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.
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.|Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Yoshihiko
Y
Noguchi
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.|Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Tomoyasu
T
Hirose
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.|Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Aki
A
Ishiyama
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.|Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Masato
M
Iwatsuki
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Kazuhiko
K
Otoguro
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. sunazuka@lisci.kitasato-u.ac.jp.|Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. sunazuka@lisci.kitasato-u.ac.jp.
Toshiaki
T
Sunazuka
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. omuras@insti.kitasato-u.ac.jp.
Satoshi
S
Ōmura
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D039821:Monoterpenes / Q000737:chemistry*; D013237:Stereoisomerism
D000962:Antimalarials; D026121:Indole Alkaloids; D039821:Monoterpenes
5-Nor stemmadenine alkaloid; Antimalarial agent; Chirality transfer intramolecular Michael reaction; Diastereoselective 1,2-addition using indole nucleophile; Iminophosphorane mediated cascade reaction; Pseudo-aminal type structure